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Journal articles on the topic 'Anti-virulence peptides'
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1
Castillo-Juárez, Israel, Blanca Esther Blancas-Luciano, Rodolfo García-Contreras, and Ana María Fernández-Presas. "Antimicrobial peptides properties beyond growth inhibition and bacterial killing." PeerJ 10 (January 21, 2022): e12667. http://dx.doi.org/10.7717/peerj.12667.
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Antimicrobial peptides (AMPs) are versatile molecules with broad antimicrobial activity produced by representatives of the three domains of life. Also, there are derivatives of AMPs and artificial short peptides that can inhibit microbial growth. Beyond killing microbes, AMPs at grow sub-inhibitory concentrations also exhibit anti-virulence activity against critical pathogenic bacteria, including ESKAPE pathogens. Anti-virulence therapies are an alternative to antibiotics since they do not directly affect viability and growth, and they are considered less likely to generate resistance. Bacterial biofilms significantly increase antibiotic resistance and are linked to establishing chronic infections. Various AMPs can kill biofilm cells and eradicate infections in animal models. However, some can inhibit biofilm formation and promote dispersal at sub-growth inhibitory concentrations. These examples are discussed here, along with those of peptides that inhibit the expression of traits controlled by quorum sensing, such as the production of exoproteases, phenazines, surfactants, toxins, among others. In addition, specific targets that are determinants of virulence include secretion systems (type II, III, and VI) responsible for releasing effector proteins toxic to eukaryotic cells. This review summarizes the current knowledge on the anti-virulence properties of AMPs and the future directions of their research.
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Artini, Marco, Esther Imperlini, Francesco Buonocore, Michela Relucenti, Fernando Porcelli, Orlando Donfrancesco, Vanessa Tuccio Guarna Assanti, Ersilia Vita Fiscarelli, Rosanna Papa, and Laura Selan. "Anti-Virulence Potential of a Chionodracine-Derived Peptide against Multidrug-Resistant Pseudomonas aeruginosa Clinical Isolates from Cystic Fibrosis Patients." International Journal of Molecular Sciences 23, no. 21 (November 4, 2022): 13494. http://dx.doi.org/10.3390/ijms232113494.
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Pseudomonas aeruginosa is an opportunistic pathogen causing several chronic infections resistant to currently available antibiotics. Its pathogenicity is related to the production of different virulence factors such as biofilm and protease secretion. Pseudomonas communities can persist in biofilms that protect bacterial cells from antibiotics. Hence, there is a need for innovative approaches that are able to counteract these virulence factors, which play a pivotal role, especially in chronic infections. In this context, antimicrobial peptides are emerging drugs showing a broad spectrum of antibacterial activity. Here, we tested the anti-virulence activity of a chionodracine-derived peptide (KHS-Cnd) on five P. aeruginosa clinical isolates from cystic fibrosis patients. We demonstrated that KHS-Cnd impaired biofilm development and caused biofilm disaggregation without affecting bacterial viability in nearly all of the tested strains. Ultrastructural morphological analysis showed that the effect of KHS-Cnd on biofilm could be related to a different compactness of the matrix. KHS-Cnd was also able to reduce adhesion to pulmonary cell lines and to impair the invasion of host cells by P. aeruginosa. A cytotoxic effect of KHS-Cnd was observed only at the highest tested concentration. This study highlights the potential of KHS-Cnd as an anti-biofilm and anti-virulence molecule against P. aeruginosa clinical strains.
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Kamli, Majid, Jamal Sabir, Maqsood Malik, and Aijaz Ahmad. "Characterization of Defensin-Like Protein 1 for Its Anti-Biofilm and Anti-Virulence Properties for the Development of Novel Antifungal Drug against Candida auris." Journal of Fungi 8, no. 12 (December 14, 2022): 1298. http://dx.doi.org/10.3390/jof8121298.
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Candida auris has emerged as a pan-resistant pathogenic yeast among immunocompromised patients worldwide. As this pathogen is involved in biofilm-associated infections with serious medical manifestations due to the collective expression of pathogenic attributes and factors associated with drug resistance, successful treatment becomes a major concern. In the present study, we investigated the candidicidal activity of a plant defensin peptide named defensin-like protein 1 (D-lp1) against twenty-five clinical strains of C. auris. Furthermore, following the standard protocols, the D-lp1 was analyzed for its anti-biofilm and anti-virulence properties. The impact of these peptides on membrane integrity was also evaluated. For cytotoxicity determination, a hemolytic assay was conducted using horse blood. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values ranged from 0.047–0.78 mg/mL and 0.095–1.56 mg/mL, respectively. D-lp1 at sub-inhibitory concentrations potentially abrogated both biofilm formation and 24-h mature biofilms. Similarly, the peptide severely impacted virulence attributes in the clinical strain of C. auris. For the insight mechanism, D-lp1 displayed a strong impact on the cell membrane integrity of the test pathogen. It is important to note that D-lp1 at sub-inhibitory concentrations displayed minimal hemolytic activity against horse blood cells. Therefore, it is highly useful to correlate the anti-Candida property of D-lp1 along with anti-biofilm and anti-virulent properties against C. auris, with the aim of discovering an alternative strategy for combating serious biofilm-associated infections caused by C. auris.
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Augustyniak, Daria, Eliza Kramarska, Paweł Mackiewicz, Magdalena Orczyk-Pawiłowicz, and Fionnuala T. Lundy. "Mammalian Neuropeptides as Modulators of Microbial Infections: Their Dual Role in Defense versus Virulence and Pathogenesis." International Journal of Molecular Sciences 22, no. 7 (April 1, 2021): 3658. http://dx.doi.org/10.3390/ijms22073658.
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The regulation of infection and inflammation by a variety of host peptides may represent an evolutionary failsafe in terms of functional degeneracy and it emphasizes the significance of host defense in survival. Neuropeptides have been demonstrated to have similar antimicrobial activities to conventional antimicrobial peptides with broad-spectrum action against a variety of microorganisms. Neuropeptides display indirect anti-infective capacity via enhancement of the host’s innate and adaptive immune defense mechanisms. However, more recently concerns have been raised that some neuropeptides may have the potential to augment microbial virulence. In this review we discuss the dual role of neuropeptides, perceived as a double-edged sword, with antimicrobial activity against bacteria, fungi, and protozoa but also capable of enhancing virulence and pathogenicity. We review the different ways by which neuropeptides modulate crucial stages of microbial pathogenesis such as adhesion, biofilm formation, invasion, intracellular lifestyle, dissemination, etc., including their anti-infective properties but also detrimental effects. Finally, we provide an overview of the efficacy and therapeutic potential of neuropeptides in murine models of infectious diseases and outline the intrinsic host factors as well as factors related to pathogen adaptation that may influence efficacy.
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Abril, Ana G., Mónica Carrera, Karola Böhme, Jorge Barros-Velázquez, José-Luis R. Rama, Pilar Calo-Mata, Angeles Sánchez-Pérez, and Tomás G. Villa. "Proteomic Characterization of Antibiotic Resistance, and Production of Antimicrobial and Virulence Factors in Streptococcus Species Associated with Bovine Mastitis. Could Enzybiotics Represent Novel Therapeutic Agents Against These Pathogens?" Antibiotics 9, no. 6 (June 4, 2020): 302. http://dx.doi.org/10.3390/antibiotics9060302.
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Streptococcus spp. are major mastitis pathogens present in dairy products, which produce a variety of virulence factors that are involved in streptococcal pathogenicity. These include neuraminidase, pyrogenic exotoxin, and M protein, and in addition they might produce bacteriocins and antibiotic-resistance proteins. Unjustifiable misuse of antimicrobials has led to an increase in antibiotic-resistant bacteria present in foodstuffs. Identification of the mastitis-causing bacterial strain, as well as determining its antibiotic resistance and sensitivity is crucial for effective therapy. The present work focused on the LC–ESI–MS/MS (liquid chromatography–electrospray ionization tandem mass spectrometry) analysis of tryptic digestion peptides from mastitis-causing Streptococcus spp. isolated from milk. A total of 2706 non-redundant peptides belonging to 2510 proteins was identified and analyzed. Among them, 168 peptides were determined, representing proteins that act as virulence factors, toxins, anti-toxins, provide resistance to antibiotics that are associated with the production of lantibiotic-related compounds, or play a role in the resistance to toxic substances. Protein comparisons with the NCBI database allowed the identification of 134 peptides as specific to Streptococcus spp., while two peptides (EATGNQNISPNLTISNAQLNLEDKNK and DLWC*NM*IIAAK) were found to be species-specific to Streptococcus dysgalactiae. This proteomic repository might be useful for further studies and research work, as well as for the development of new therapeutics for the mastitis-causing Streptococcus strains.
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Abril, Ana G., Mónica Carrera, Karola Böhme, Jorge Barros-Velázquez, Pilar Calo-Mata, Angeles Sánchez-Pérez, and Tomás G. Villa. "Proteomic Characterization of Antibiotic Resistance in Listeria and Production of Antimicrobial and Virulence Factors." International Journal of Molecular Sciences 22, no. 15 (July 29, 2021): 8141. http://dx.doi.org/10.3390/ijms22158141.
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Some Listeria species are important human and animal pathogens that can be found in contaminated food and produce a variety of virulence factors involved in their pathogenicity. Listeria strains exhibiting multidrug resistance are known to be progressively increasing and that is why continuous monitoring is needed. Effective therapy against pathogenic Listeria requires identification of the bacterial strain involved, as well as determining its virulence factors, such as antibiotic resistance and sensitivity. The present study describes the use of liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS) to do a global shotgun proteomics characterization for pathogenic Listeria species. This method allowed the identification of a total of 2990 non-redundant peptides, representing 2727 proteins. Furthermore, 395 of the peptides correspond to proteins that play a direct role in Listeria pathogenicity; they were identified as virulence factors, toxins and anti-toxins, or associated with either antibiotics (involved in antibiotic-related compounds production or resistance) or resistance to toxic substances. The proteomic repository obtained here can be the base for further research into pathogenic Listeria species and facilitate the development of novel therapeutics for these pathogens.
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O'Brien-Simpson, Neil M., Rita A. Paolini, and Eric C. Reynolds. "RgpA-Kgp Peptide-Based Immunogens Provide Protection againstPorphyromonas gingivalis Challenge in a Murine Lesion Model." Infection and Immunity 68, no. 7 (July 1, 2000): 4055–63. http://dx.doi.org/10.1128/iai.68.7.4055-4063.2000.
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ABSTRACT Porphyromonas gingivalis, a gram-negative bacterium, has been linked to the onset and progression of periodontitis, a chronic inflammatory disease of the supporting tissues of the teeth. A major virulence factor ofP. gingivalis is an extracellular complex of Arg- and Lys-specific proteinases and adhesins designated the RgpA-Kgp complex (formerly the PrtR-PrtK complex). In this study we show that the RgpA-Kgp complex, when used as an immunogen with incomplete Freund adjuvant (IFA), protects against challenge with invasive and noninvasive strains of P. gingivalis in the murine lesion model. We identified a variety of peptide vaccine candidates from the RgpA and Kgp polyprotein sequences that involved the putative active site histidine of both proteinases and five repeat motifs in the adhesin domains of both polyproteins implicated in aggregation and binding to host substrates, designated adhesin-binding motif (ABM) peptides. These peptides were synthesized using standard, solid-phase protocols for 9-fluorenylmethoxy carbonyl chemistry withS-acetylmercaptoacetic acid (SAMA) as the N-terminal residue. The SAMA-peptides were then conjugated to diphtheria toxoid and used with IFA to immunize BALB/c mice. Both active-site peptides and three of the five ABM peptides gave protection (P< 0.005) against challenge with P. gingivalis in the murine lesion model. The three ABM peptide sequences that conferred protection exist within a 100-residue span in the RgpA44 and Kgp39 adhesins of the RgpA-Kgp complex. Protective anti-RgpA-Kgp complex mouse antisera recognized the RgpA27, Kgp39, and RgpA44 adhesins in an immunoblot. Epitope mapping of the RgpA27 adhesin using the protective anti-RgpA-Kgp antisera identified a major protective epitope that mapped immediately N terminal to one of the protective ABM peptides in the 100-residue span in RgpA44 and Kgp39. This identified protective epitope contains clusters of basic residues spatially surrounded by hydrophobic amino acids, a finding which is characteristic of a heparin binding motif.
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Åkesson, Per, Heiko Herwald, Magnus Rasmussen, Katarina HÅkansson, Magnus Abrahamson, Ahmed A. K. Hasan, Alvin H. Schmaier, Werner Müller-Esterl, and Lars Björck. "Streptococcal inhibitor of complement-mediated lysis (SIC): an anti-inflammatory virulence determinant." Microbiology 156, no. 12 (December 1, 2010): 3660–68. http://dx.doi.org/10.1099/mic.0.039578-0.
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Since the late 1980s, a worldwide increase of severe Streptococcus pyogenes infections has been associated with strains of the M1 serotype, strains which all secrete the streptococcal inhibitor of complement-mediated lysis (SIC). Previous work has shown that SIC blocks complement-mediated haemolysis, inhibits the activity of antibacterial peptides and has affinity for the human plasma proteins clusterin and histidine-rich glycoprotein; the latter is a member of the cystatin protein family. The present work demonstrates that SIC binds to cystatin C, high-molecular-mass kininogen (HK) and low-molecular-mass kininogen, which are additional members of this protein family. The binding sites in HK are located in the cystatin-like domain D3 and the endothelial cell-binding domain D5. Immobilization of HK to cellular structures plays a central role in activation of the human contact system. SIC was found to inhibit the binding of HK to endothelial cells, and to reduce contact activation as measured by prolonged blood clotting time and impaired release of bradykinin. These results suggest that SIC modifies host defence systems, which may contribute to the virulence of S. pyogenes strains of the M1 serotype.
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Pacios, Olga, Lucia Blasco, Inès Bleriot, Laura Fernandez-Garcia, Mónica González Bardanca, Antón Ambroa, María López, German Bou, and Maria Tomás. "Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases." Antibiotics 9, no. 2 (February 6, 2020): 65. http://dx.doi.org/10.3390/antibiotics9020065.
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Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.
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El-Dirany, Rima, Celia Fernández-Rubio, José Peña-Guerrero, Esther Moreno, Esther Larrea, Socorro Espuelas, Fadi Abdel-Sater, Klaus Brandenburg, Guillermo Martínez-de-Tejada, and Paul Nguewa. "Repurposing the Antibacterial Agents Peptide 19-4LF and Peptide 19-2.5 for Treatment of Cutaneous Leishmaniasis." Pharmaceutics 14, no. 11 (November 20, 2022): 2528. http://dx.doi.org/10.3390/pharmaceutics14112528.
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The lack of safe and cost-effective treatments against leishmaniasis highlights the urgent need to develop improved leishmanicidal agents. Antimicrobial peptides (AMPs) are an emerging category of therapeutics exerting a wide range of biological activities such as anti-bacterial, anti-fungal, anti-parasitic and anti-tumoral. In the present study, the approach of repurposing AMPs as antileishmanial drugs was applied. The leishmanicidal activity of two synthetic anti-lipopolysaccharide peptides (SALPs), so-called 19-2.5 and 19-4LF was characterized in Leishmania major. In vitro, both peptides were highly active against intracellular Leishmania major in mouse macrophages without exerting toxicity in host cells. Then, q-PCR-based gene profiling, revealed that this activity was related to the downregulation of several genes involved in drug resistance (yip1), virulence (gp63) and parasite proliferation (Cyclin 1 and Cyclin 6). Importantly, the treatment of BALB/c mice with any of the two AMPs caused a significant reduction in L. major infective burden. This effect was associated with an increase in Th1 cytokine levels (IL-12p35, TNF-α, and iNOS) in the skin lesion and spleen of the L. major infected mice while the Th2-associated genes were downregulated (IL-4 and IL-6). Lastly, we investigated the effect of both peptides in the gene expression profile of the P2X7 purinergic receptor, which has been reported as a therapeutic target in several diseases. The results showed significant repression of P2X7R by both peptides in the skin lesion of L. major infected mice to an extent comparable to that of a common anti-leishmanial drug, Paromomycin. Our in vitro and in vivo studies suggest that the synthetic AMPs 19-2.5 and 19-4LF are promising candidates for leishmaniasis treatment and present P2X7R as a potential therapeutic target in cutaneous leishmaniasis (CL).
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Baruch, Dror I., Xin C. Ma, Brittan Pasloske, Russell J. Howard, and Louis H. Miller. "CD36 Peptides That Block Cytoadherence Define the CD36 Binding Region for Plasmodium falciparum-Infected Erythrocytes." Blood 94, no. 6 (September 15, 1999): 2121–27. http://dx.doi.org/10.1182/blood.v94.6.2121.
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Abstract Mature Plasmodium falciparum parasitized erythrocytes (PE) sequester from the circulation by adhering to microvascular endothelial cells. PE sequestration contributes directly to the virulence and severe pathology of falciparum malaria. The scavenger receptor, CD36, is a major host receptor for PE adherence. PE adhesion to CD36 is mediated by the malarial variant antigen, P. falciparumerythrocyte membrane protein 1 (PfEMP1), and particularly by its cysteine-rich interdomain region 1 (CIDR-1). Several peptides from the extended immunodominant domain of CD36 (residues 139-184), including CD36 139-155, CD36 145-171, CD36 146-164, and CD36 156-184 interfered with the CD36-PfEMP1 interaction. Each of these peptides affected binding at the low micromolar range in 2 independent assays. Two peptides, CD36 145-171 and CD36 156-184, specifically blocked PE adhesion to CD36 without affecting binding to the host receptor intercellular adhesion molecule-1 (ICAM-1). Moreover, an adhesion blocking peptide from the ICAM-1 sequence inhibits the PfEMP1–ICAM-1 interaction without affecting adhesion to CD36. These results confirm earlier observations that PfEMP1 is also a receptor for ICAM-1. Thus, the region 139-184 and particularly the 146-164 or the 145-171 regions of CD36 form the adhesion region for P. falciparum PE. Adherence blocking peptides from this region may be useful for modeling the PE/PfEMP1 interaction with CD36 and for development of potential anti-adhesion therapeutics.
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Baruch, Dror I., Xin C. Ma, Brittan Pasloske, Russell J. Howard, and Louis H. Miller. "CD36 Peptides That Block Cytoadherence Define the CD36 Binding Region for Plasmodium falciparum-Infected Erythrocytes." Blood 94, no. 6 (September 15, 1999): 2121–27. http://dx.doi.org/10.1182/blood.v94.6.2121.418k09_2121_2127.
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Mature Plasmodium falciparum parasitized erythrocytes (PE) sequester from the circulation by adhering to microvascular endothelial cells. PE sequestration contributes directly to the virulence and severe pathology of falciparum malaria. The scavenger receptor, CD36, is a major host receptor for PE adherence. PE adhesion to CD36 is mediated by the malarial variant antigen, P. falciparumerythrocyte membrane protein 1 (PfEMP1), and particularly by its cysteine-rich interdomain region 1 (CIDR-1). Several peptides from the extended immunodominant domain of CD36 (residues 139-184), including CD36 139-155, CD36 145-171, CD36 146-164, and CD36 156-184 interfered with the CD36-PfEMP1 interaction. Each of these peptides affected binding at the low micromolar range in 2 independent assays. Two peptides, CD36 145-171 and CD36 156-184, specifically blocked PE adhesion to CD36 without affecting binding to the host receptor intercellular adhesion molecule-1 (ICAM-1). Moreover, an adhesion blocking peptide from the ICAM-1 sequence inhibits the PfEMP1–ICAM-1 interaction without affecting adhesion to CD36. These results confirm earlier observations that PfEMP1 is also a receptor for ICAM-1. Thus, the region 139-184 and particularly the 146-164 or the 145-171 regions of CD36 form the adhesion region for P. falciparum PE. Adherence blocking peptides from this region may be useful for modeling the PE/PfEMP1 interaction with CD36 and for development of potential anti-adhesion therapeutics.
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Jakob, Valentin, Ben G. E. Zoller, Julia Rinkes, Yingwen Wu, Alexander F. Kiefer, Michael Hust, Saskia Polten, et al. "Phage display-based discovery of cyclic peptides against the broad spectrum bacterial anti-virulence target CsrA." European Journal of Medicinal Chemistry 231 (March 2022): 114148. http://dx.doi.org/10.1016/j.ejmech.2022.114148.
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Al Akeel, Raid, Ayesha Mateen, and Rabbani Syed. "An Alanine-Rich Peptide Attenuates Quorum Sensing-Regulated Virulence and Biofilm Formation in Staphylococcus aureus." Journal of AOAC INTERNATIONAL 102, no. 4 (July 1, 2019): 1228–34. http://dx.doi.org/10.5740/jaoacint.18-0251.
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Abstract Background: Alanine-rich proteins/peptides (ARP), with bioactivity of up to 20 amino acid residues, can be observed by the body easily during gastrointestinal digestion. Objective: Populus trichocarpa extract’s capability to attenuate quorum sensing-regulated virulence and biofilm formation in Staphylococcus aureus is described. Methods: PT13, an ARP obtained from P. trichocarpa, was tested for its activity against S. aureus using the broth microdilution test; a crystal-violet biofilm assay was performed under a scanning electron microscope. The production of various virulence factors was estimated with PT13 treatment. Microarray gene expression profiling of PT13-treated S. aureus was conducted and compared with an untreated control. Exopolysaccharides (EPS) was estimated to observe the PT13 inhibition activity. Results: PT13 was antimicrobial toward S. aureus at different concentrations and showed a similar growth rate in the presence and absence of PT13 at concentrations ≤8 μg/mL. Biofilm production was interrupted even at low concentrations, and biofilm-related genes were down-regulated when exposed to PT13. The genes encoding cell adhesion and bacterial attachment protein were the major genes suppressed by PT13. In addition, hemolysins, clumping activity, and EPS production of S. aureus decreased after treatment in a concentration-dependent manner. Conclusions: A long-chain PT13 with effective actions that, even at low concentration levels, not only regulated the gene expression in the producer organism but also blocked the virulence gene expression in this Gram-positive human pathogen is described. Highlights: We identified a PT13 as a potential antivirulence agent that regulated production of bacterial virulence determinants (e.g., toxins, enzymes and biofilm), downwards and it may be a promising anti-virulence agent to be further developed as an anti-infective agent.
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O’Callaghan, Richard, Armando Caballero, Aihua Tang, and Michael Bierdeman. "Pseudomonas aeruginosa Keratitis: Protease IV and PASP as Corneal Virulence Mediators." Microorganisms 7, no. 9 (August 22, 2019): 281. http://dx.doi.org/10.3390/microorganisms7090281.
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Pseudomonas aeruginosa is a leading cause of bacterial keratitis, especially in users of contact lenses. These infections are characterized by extensive degradation of the corneal tissue mediated by Pseudomonas protease activities, including both Pseudomonas protease IV (PIV) and the P. aeruginosa small protease (PASP). The virulence role of PIV was determined by the reduced virulence of a PIV-deficient mutant relative to its parent strain and the mutant after genetic complementation (rescue). Additionally, the non-ocular pathogen Pseudomonas putida acquired corneal virulence when it produced active PIV from a plasmid-borne piv gene. The virulence of PIV is not limited to the mammalian cornea, as evidenced by its destruction of respiratory surfactant proteins and the cytokine interleukin-22 (IL-22), the key inducer of anti-bacterial peptides. Furthermore, PIV contributes to the P. aeruginosa infection of both insects and plants. A possible limitation of PIV is its inefficient digestion of collagens; however, PASP, in addition to cleaving multiple soluble proteins, is able to efficiently cleave collagens. A PASP-deficient mutant lacks the corneal virulence of its parent or rescue strain evidencing its contribution to corneal damage, especially epithelial erosion. Pseudomonas-secreted proteases contribute importantly to infections of the cornea, mammalian lung, insects, and plants.
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Alharthi, Sitah, Amirali Popat, Zyta Maria Ziora, and Peter Michael Moyle. "Sortase A Inhibitor Protein Nanoparticle Formulations Demonstrate Antibacterial Synergy When Combined with Antimicrobial Peptides." Molecules 28, no. 5 (February 24, 2023): 2114. http://dx.doi.org/10.3390/molecules28052114.
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Sortase A (SrtA) is an enzyme which attaches proteins, including virulence factors, to bacterial cell walls. It is a potential target for developing anti-virulence agents against pathogenic and antimicrobial resistant bacteria. This study aimed to engineer 𝛽-lactoglobulin protein nanoparticles (PNPs) for encapsulating safe and inexpensive natural SrtA inhibitors (SrtAIs; trans-chalcone (TC), curcumin (CUR), quercetin (QC), and berberine (BR)) to improve their poor aqueous dispersibility, to screen for synergy with antimicrobial peptides (AMPs), and to reduce the cost, dose, and toxicity of AMPs. Minimum inhibitory concentration (MIC), checkerboard synergy, and cell viability assays were performed for SrtAI PNPs against Gram-positive (methicillin-sensitive and -resistant S. aureus) and Gram-negative (E. coli, P. aeruginosa) bacteria alone and combined with leading AMPs (pexiganan, indolicidin, and a mastoparan derivative). Each SrtAI PNP inhibited Gram-positive (MIC: 62.5–125 µg/mL) and Gram-negative (MIC: 31.3–500 µg/mL) bacterial growth. TC PNPs with pexiganan demonstrated synergy against each bacteria, while BR PNPs with pexiganan or indolicidin provided synergy towards S. aureus. Each SrtAI PNP inhibited SrtA (IC50: 25.0–81.8 µg/mL), and did not affect HEK-293 cell viability at their MIC or optimal synergistic concentrations with AMPs. Overall, this study provides a safe nanoplatform for enhancing antimicrobial synergy to develop treatments for superbug infections.
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Cooray, Samantha, Mohammad W. Bahar, Nicola G. A. Abrescia, Colin E. McVey, Nathan W. Bartlett, Ron A. J. Chen, David I. Stuart, Jonathan M. Grimes, and Geoffrey L. Smith. "Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein." Journal of General Virology 88, no. 6 (June 1, 2007): 1656–66. http://dx.doi.org/10.1099/vir.0.82772-0.
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Vaccinia virus (VACV) encodes many immunomodulatory proteins, including inhibitors of apoptosis and modulators of innate immune signalling. VACV protein N1 is an intracellular homodimer that contributes to virus virulence and was reported to inhibit nuclear factor (NF)-κB signalling. However, analysis of NF-κB signalling in cells infected with recombinant viruses with or without the N1L gene showed no difference in NF-κB-dependent gene expression. Given that N1 promotes virus virulence, other possible functions of N1 were investigated and this revealed that N1 is an inhibitor of apoptosis in cells transfected with the N1L gene and in the context of VACV infection. In support of this finding virally expressed N1 co-precipitated with endogenous pro-apoptotic Bcl-2 proteins Bid, Bad and Bax as well as with Bad and Bax expressed by transfection. In addition, the crystal structure of N1 was solved to 2.9 Å resolution (0.29 nm). Remarkably, although N1 shows no sequence similarity to cellular proteins, its three-dimensional structure closely resembles Bcl-xL and other members of the Bcl-2 protein family. The structure also reveals that N1 has a constitutively open surface groove similar to the grooves of other anti-apoptotic Bcl-2 proteins, which bind the BH3 motifs of pro-apoptotic Bcl-2 family members. Molecular modelling of BH3 peptides into the N1 surface groove, together with analysis of their physico-chemical properties, suggests a mechanism for the specificity of peptide recognition. This study illustrates the importance of the evolutionary conservation of structure, rather than sequence, in protein function and reveals a novel anti-apoptotic protein from orthopoxviruses.
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Simonetti, Oriana, Giulio Rizzetto, Giulia Radi, Elisa Molinelli, Oscar Cirioni, Andrea Giacometti, and Annamaria Offidani. "New Perspectives on Old and New Therapies of Staphylococcal Skin Infections: The Role of Biofilm Targeting in Wound Healing." Antibiotics 10, no. 11 (November 10, 2021): 1377. http://dx.doi.org/10.3390/antibiotics10111377.
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Among the most common complications of both chronic wound and surgical sites are staphylococcal skin infections, which slow down the wound healing process due to various virulence factors, including the ability to produce biofilms. Furthermore, staphylococcal skin infections are often caused by methicillin-resistant Staphylococcus aureus (MRSA) and become a therapeutic challenge. The aim of this narrative review is to collect the latest evidence on old and new anti-staphylococcal therapies, assessing their anti-biofilm properties and their effect on skin wound healing. We considered antibiotics, quorum sensing inhibitors, antimicrobial peptides, topical dressings, and antimicrobial photo-dynamic therapy. According to our review of the literature, targeting of biofilm is an important therapeutic choice in acute and chronic infected skin wounds both to overcome antibiotic resistance and to achieve better wound healing.
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Salcines-Cuevas, David, Hector Terán-Navarro, Ricardo Calderón-Gonzalez, Paula Torres-Rodriguez, Raquel Tobes, Manuel Fresno, Jorge Calvo-Montes, I. Concepción Pérez Del Molino-Bernal, Sonsoles Yañez-Diaz, and Carmen Alvarez-Dominguez. "Glyceraldehyde-3-phosphate Dehydrogenase Common Peptides of Listeria monocytogenes, Mycobacterium marinum and Streptococcus pneumoniae as Universal Vaccines." Vaccines 9, no. 3 (March 17, 2021): 269. http://dx.doi.org/10.3390/vaccines9030269.
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Universal vaccines can be prepared with antigens common to different pathogens. In this regard, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a common virulence factor among pathogenic bacteria of the genera Listeria, Mycobacterium and Streptococcus. Their N-terminal 22 amino acid peptides, GAPDH-L1 (Listeria), GAPDH-M1 (Mycobacterium) and GAPDH-S1 (Streptococcus), share 95–98.55% sequence homology, biochemical and MHC binding abilities and, therefore, are good candidates for universal vaccine designs. Here, we used dendritic cells (DC) as vaccine platforms to test GAPDH epitopes that conferred protection against Listeria monocytogenes, Mycobacterium marinum or Streptococcus pneumoniae in our search of epitopes for universal vaccines. DC loaded with GAPDH-L1, GAPDH-M1 or GAPDH-S1 peptides show high immunogenicity measured by the cellular DTH responses in mice, lacked toxicity and were capable of cross-protection immunity against mice infections with each one of the pathogens. Vaccine efficiency correlated with high titers of anti-GAPDH-L1 antibodies in sera of vaccinated mice, a Th1 cytokine pattern and high frequencies of GAPDH-L1-specific CD4+ and CD8+ T cells and IFN-γ producers in the spleens. We concluded that GAPDH-L1 peptide was the best epitope for universal vaccines in the Listeria, Mycobacterium or Streptococcus taxonomic groups, whose pathogenic strains caused relevant morbidities in adults and especially in the elderly.
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Castellar, C., D. M. Castillo, L. Chila, W. Bautista-Molano, J. M. Bello-Gualtero, and C. Romero-Sánchez. "AB0086 PORPHYROMONAS GULAE INFECTION IS NOT RELATED TO EXOGENOUS CITRULINATION OR DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1174.2–1175. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4179.
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BackgroundPorphyromonas gulae (P. gulae) is a Gram negative microorganism of the Porphyromonadaceae family. It presents in its structure virulence factors similar to P. gingivalis, including the PAD enzyme. An enzyme responsible for catalyzing citrullination, related to the formation of autoantibodies against citrullinated peptides associated with Rheumatoid Arthritis (RA).ObjectivesTo evaluate the presence of P. gulae and anti-citrullinated peptide antibodies of P. gulae PAD in patients with RA and their possible association with clinical markers of activity.MethodsNinety RA patients and 90 controls matched for age and sex were included. Serum levels of rheumatological markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-citrullinated protein antibodies (Anti-CCp/ACPA) and rheumatoid factor (RF) were measured. Disease activity was assessed using Disease Activity Indices-28 (DAS28) and SCDAI. The periodontal diagnosis was according to CDC and American Academy of Periodontology. The presence of P. gulae was established by qPCR, verifying the specificity and confirmed due to the high homology between P. gingivalis and P. gulae. The presence of antibodies against 2 peptides called VDK and LPQ were evaluated in their native structure and citrullinated at one end and inside the PPAD molecule of P.gulae. It was determined by ELISA in-house. Prediction of B and T epitopes of PPAD from P. gulae was made taking into account the location of arginines within the molecule, restricting it to HLA alleles associated with RA. Associations were established by Kruskal Wallis, Mann Whitney U tests and multiple correspondence discriminant analysis (MCDA) in SPSS V24 and STATA for Windows software, with a significance of 95%,p≤ 0.05.ResultsA frequency of P. gulae was observed in the RA group of 15.8% versus controls of 9.5%, p=0.1925, A Despite finding a diagnosis of periodontitis in 70.5% of the patients, it was not associated with clinical severity or diagnosis of periodontitis. Comparisons were made classifying the patients according to periodontal diagnosis, the presence of P. gulae was observed more frequently in the RA group with a diagnosis of periodontitis, compared to the control group (6.7% vs 2.5%, respectively) without statistical significance (p=0.2576).Of the 180 individuals evaluated, 17 had the presence of anti-citrullinated peptide antibodies of P. gulae PAD. Despite a higher frequency in the RA group of antibodies against two citrullinated peptides, the results were not significant (p=0.378 and p=0.346), there was no evidence of a relationship with activity or disease markers in RA. The MCDA test generated two dimensions, one with the clinical activity variables of RA with CC: 0.218, and a second dimension in which the presence of anti-citrullinated peptide antibodies of PAD CC were related to each other CC: 0.749; No positive correlation was found between the clinical variables of RA and the anti-citrullinated peptide antibodies of P. gulae PAD.ConclusionDespite the presence of P. gulae and PPAD citrullinated peptide antibodies from P. gulae in patients with RA, it was not possible to establish the relationship with clinical variables, which could indicate a lower contribution of this microorganismto the biological mechanism and molecular of citrullination common between RA and periodontitis. However, an additive effect of P. gulae with P. gingivalis in the citrullination process cannot be ruled out.AcknowledgementsThe Ministry of Science, Technology, and Innovation - MinCiencias (Grants No. 55642, 531734 and 740792). Universidad El Bosque (PCI-2018-10441), Hospital Militar Central and Fundación Instituto de Reumatología Fernando Chalem, in Bogota, Colombia.Disclosure of InterestsNone declared
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Calcagnile, Matteo, Inès Jeguirim, Salvatore Maurizio Tredici, Fabrizio Damiano, and Pietro Alifano. "Spiramycin Disarms Pseudomonas aeruginosa without Inhibiting Growth." Antibiotics 12, no. 3 (March 2, 2023): 499. http://dx.doi.org/10.3390/antibiotics12030499.
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Spiramycin is a 16-membered macrolide antibiotic currently used in therapy to treat infections caused by Gram-positive bacteria responsible for respiratory tract infections, and it is also effective against some Gram-negative bacteria and against Toxoplasma spp. In contrast, Pseudomonas aeruginosa, which is one of the pathogens of most concern globally, is intrinsically resistant to spiramycin. In this study we show that spiramycin inhibits the expression of virulence determinants in P. aeruginosa in the absence of any significant effect on bacterial multiplication. In vitro experiments demonstrated that production of pyoverdine and pyocyanin by an environmental strain of P. aeruginosa was markedly reduced in the presence of spiramycin, as were biofilm formation, swarming motility, and rhamnolipid production. Moreover, treatment of P. aeruginosa with spiramycin sensitized the bacterium to H2O2 exposure. The ability of spiramycin to dampen the virulence of the P. aeruginosa strain was confirmed in a Galleria mellonella animal model. The results demonstrated that when G. mellonella larvae were infected with P. aeruginosa, the mortality after 24 h was >90%. In contrast, when the spiramycin was injected together with the bacterium, the mortality dropped to about 50%. Furthermore, marked reduction in transcript levels of the antimicrobial peptides gallerimycin, gloverin and moricin, and lysozyme was found in G. mellonella larvae infected with P. aeruginosa and treated with spiramycin, compared to the larvae infected without spiramycin treatment suggesting an immunomodulatory activity of spiramycin. These results lay the foundation for clinical studies to investigate the possibility of using the spiramycin as an anti-virulence and anti-inflammatory drug for a more effective treatment of P. aeruginosa infections, in combination with other antibiotics.
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Huang, Xueting, Xiuyuan Li, Haoran An, Juanjuan Wang, Ming Ding, Lijun Wang, Lulu Li, et al. "Capsule type defines the capability of Klebsiella pneumoniae in evading Kupffer cell capture in the liver." PLOS Pathogens 18, no. 8 (August 1, 2022): e1010693. http://dx.doi.org/10.1371/journal.ppat.1010693.
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Polysaccharide capsule is the main virulence factor of K. pneumoniae, a major pathogen of bloodstream infections in humans. While more than 80 capsular serotypes have been identified in K. pneumoniae, only several serotypes are frequently identified in invasive infections. It is documented that the capsule enhances bacterial resistance to phagocytosis, antimicrobial peptides and complement deposition under in vitro conditions. However, the precise role of the capsule in the process of K. pneumoniae bloodstream infections remains to be elucidated. Here we show that the capsule promotes K. pneumoniae survival in the bloodstream by protecting bacteria from being captured by liver resident macrophage Kupffer cells (KCs). Our real-time in vivo imaging revealed that blood-borne acapsular K. pneumoniae mutant is rapidly captured and killed by KCs in the liver sinusoids of mice, whereas, to various extents, encapsulated strains bypass the anti-bacterial machinery in a serotype-dependent manner. Using capsule switched strains, we show that certain high-virulence (HV) capsular serotypes completely block KC’s capture, whereas the low-virulence (LV) counterparts confer partial protection against KC’s capture. Moreover, KC’s capture of the LV K. pneumoniae could be in vivo neutralized by free capsular polysaccharides of homologous but not heterologous serotypes, indicating that KCs specifically recognize the LV capsules. Finally, immunization with inactivated K. pneumoniae enables KCs to capture the HV K. pneumoniae. Together, our findings have uncovered that KCs are the major target cells of K. pneumoniae capsule to promote bacterial survival and virulence, which can be reversed by vaccination.
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Nguyen, Melissa L., Sherry R. Crowe, Sridevi Kurella, Simon Teryzan, Brian Cao, Jimmy D. Ballard, Judith A. James, and A. Darise Farris. "Sequential B-Cell Epitopes of Bacillus anthracis Lethal Factor Bind Lethal Toxin-Neutralizing Antibodies." Infection and Immunity 77, no. 1 (November 3, 2008): 162–69. http://dx.doi.org/10.1128/iai.00788-08.
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ABSTRACT The bipartite anthrax lethal toxin (LeTx) consisting of protective antigen (PA) and lethal factor (LF) is a major virulence factor contributing to death from systemic Bacillus anthracis infection. The current vaccine elicits antibodies directed primarily to PA; however, in experimental settings serologic responses to LF can neutralize LeTx and contribute to protection against infection. The goals of the present study were to identify sequential B-cell epitopes of LF and to determine the capacity of these determinants to bind neutralizing antibodies. Sera of recombinant LF-immunized A/J mice exhibited high titers of immunoglobulin G anti-LF reactivity that neutralized LeTx in vitro 78 days after the final booster immunization and protected the mice from in vivo challenge with 3 50% lethal doses of LeTx. These sera bound multiple discontinuous epitopes, and there were major clusters of reactivity on native LF. Strikingly, all three neutralizing, LF-specific monoclonal antibodies tested bound specific peptide sequences that coincided with sequential epitopes identified in polyclonal antisera from recombinant LF-immunized mice. This study confirms that LF induces high-titer protective antibodies in vitro and in vivo. Moreover, the binding of short LF peptides by LF-specific neutralizing monoclonal antibodies suggests that generation of protective antibodies by peptide vaccination may be feasible for this antigen. This study paves the way for a more effective anthrax vaccine by identifying discontinuous peptide epitopes of LF.
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Motiwala, Tehrim, Qiniso Mthethwa, Ikechukwu Achilonu, and Thandeka Khoza. "ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets." Antibiotics 11, no. 9 (September 8, 2022): 1218. http://dx.doi.org/10.3390/antibiotics11091218.
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Bacterial antibiotic resistance is rapidly growing globally and poses a severe health threat as the number of multidrug resistant (MDR) and extensively drug-resistant (XDR) bacteria increases. The observed resistance is partially due to natural evolution and to a large extent is attributed to antibiotic misuse and overuse. As the rate of antibiotic resistance increases, it is crucial to develop new drugs to address the emergence of MDR and XDR pathogens. A variety of strategies are employed to address issues pertaining to bacterial antibiotic resistance and these strategies include: (1) the anti-virulence approach, which ultimately targets virulence factors instead of killing the bacterium, (2) employing antimicrobial peptides that target key proteins for bacterial survival and, (3) phage therapy, which uses bacteriophages to treat infectious diseases. In this review, we take a renewed look at a group of ESKAPE pathogens which are known to cause nosocomial infections and are able to escape the bactericidal actions of antibiotics by reducing the efficacy of several known antibiotics. We discuss previously observed escape mechanisms and new possible therapeutic measures to combat these pathogens and further suggest caseinolytic proteins (Clp) as possible therapeutic targets to combat ESKAPE pathogens. These proteins have displayed unmatched significance in bacterial growth, viability and virulence upon chronic infection and under stressful conditions. Furthermore, several studies have showed promising results with targeting Clp proteins in bacterial species, such as Mycobacterium tuberculosis, Staphylococcus aureus and Bacillus subtilis.
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Zarzosa-Moreno, Daniela, Christian Avalos-Gómez, Luisa Sofía Ramírez-Texcalco, Erick Torres-López, Ricardo Ramírez-Mondragón, Juan Omar Hernández-Ramírez, Jesús Serrano-Luna, and Mireya de la Garza. "Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens." Molecules 25, no. 24 (December 8, 2020): 5763. http://dx.doi.org/10.3390/molecules25245763.
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Due to the emergence of multidrug-resistant pathogens, it is necessary to develop options to fight infections caused by these agents. Lactoferrin (Lf) is a cationic nonheme multifunctional glycoprotein of the innate immune system of mammals that provides numerous benefits. Lf is bacteriostatic and/or bactericidal, can stimulate cell proliferation and differentiation, facilitate iron absorption, improve neural development and cognition, promote bone growth, prevent cancer and exert anti-inflammatory and immunoregulatory effects. Lactoferrin is present in colostrum and milk and is also produced by the secondary granules of polymorphonuclear leukocytes, which store this glycoprotein and release it at sites of infection. Lf is also present in many fluids and exocrine secretions, on the surfaces of the digestive, respiratory and reproductive systems that are commonly exposed to pathogens. Apo-Lf (an iron-free molecule) can be microbiostatic due to its ability to capture ferric iron, blocking the availability of host iron to pathogens. However, apo-Lf is mostly microbicidal via its interaction with the microbial surface, causing membrane damage and altering its permeability function. Lf can inhibit viral entry by binding to cell receptors or viral particles. Lf is also able to counter different important mechanisms evolved by microbial pathogens to infect and invade the host, such as adherence, colonization, invasion, production of biofilms and production of virulence factors such as proteases and toxins. Lf can also cause mitochondrial and caspase-dependent regulated cell death and apoptosis-like in pathogenic yeasts. All of these mechanisms are important targets for treatment with Lf. Holo-Lf (the iron-saturated molecule) can contain up to two ferric ions and can also be microbicidal against some pathogens. On the other hand, lactoferricins (Lfcins) are peptides derived from the N-terminus of Lf that are produced by proteolysis with pepsin under acidic conditions, and they cause similar effects on pathogens to those caused by the parental Lf. Synthetic analog peptides comprising the N-terminus Lf region similarly exhibit potent antimicrobial properties. Importantly, there are no reported pathogens that are resistant to Lf and Lfcins; in addition, Lf and Lfcins have shown a synergistic effect with antimicrobial and antiviral drugs. Due to the Lf properties being microbiostatic, microbicidal, anti-inflammatory and an immune modulator, it represents an excellent natural alternative either alone or as adjuvant in the combat to antibiotic multidrug-resistant bacteria and other pathogens. This review aimed to evaluate the data that appeared in the literature about the effects of Lf and its derived peptides on pathogenic bacteria, protozoa, fungi and viruses and how Lf and Lfcins inhibit the mechanisms developed by these pathogens to cause disease.
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Wilson, Dan R., Annette Siebers, and B. Brett Finlay. "Antigenic Analysis of Bordetella pertussis Filamentous Hemagglutinin with Phage Display Libraries and Rabbit Anti-Filamentous Hemagglutinin Polyclonal Antibodies." Infection and Immunity 66, no. 10 (October 1, 1998): 4884–94. http://dx.doi.org/10.1128/iai.66.10.4884-4894.1998.
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ABSTRACT Although substantial advancements have been made in the development of efficacious acellular vaccines against Bordetella pertussis, continued progress requires better understanding of the antigenic makeup of B. pertussis virulence factors, including filamentous hemagglutinin (FHA). To identify antigenic regions of FHA, phage display libraries constructed by using random fragments of the 10-kbp EcoRI fragment ofB. pertussis fhaB were affinity selected with rabbit anti-FHA polyclonal antibodies. Characterization of antibody-reactive clones displaying FHA-derived peptides identified 14 antigenic regions, each containing one or more epitopes. A number of clones mapped within regions containing known or putative FHA adhesin domains and may be relevant for the generation of protective antibodies. The immunogenic potential of the phage-displayed peptides was assessed indirectly by comparing their recognition by antibodies elicited by sodium dodecyl sulfate (SDS)-denatured and native FHA and by measuring the inhibition of this recognition by purified FHA. FHA residues 1929 to 2019 may contain the most dominant linear epitope of FHA. Clones mapping to this region accounted for ca. 20% of clones recovered from the initial library selection and screening procedures. They are strongly recognized by sera against both SDS-denatured and native FHA, and this recognition is readily inhibited by purified FHA. Given also that this region includes a factor X homolog (J. Sandros and E. Tuomanen, Trends Microbiol. 1:192–196, 1993) and that the single FHA epitope (residues 2001 to 2015) was unequivocally defined in a comparable study by E. Leininger et al. (J. Infect. Dis. 175:1423–1431, 1997), peptides derived from residues of 1929 to 2019 of FHA are strong candidates for future protection studies.
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Moutaftsi, Magdalini, Huynh-Hoa Bui, Bjoern Peters, John Sidney, Shahram Salek-Ardakani, Carla Oseroff, Valerie Pasquetto, et al. "Vaccinia Virus-specific CD4+ T cell Responses Target a Set of Antigens Largely Distinct from those Targeted by CD8+ T cell Responses (43.34)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S43. http://dx.doi.org/10.4049/jimmunol.178.supp.43.34.
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Abstract Vaccinia virus (VACV) is a potent and effective vaccine, inducing long-lasting protective cellular immune responses. Recent studies defined the antigens recognized in mice and humans by CD8+ T cell responses. However, little is known about the specificities of CD4+ T cell responses, which makes it problematic to study and monitor cellular immune responses to VACV infections. Herein, we report for the first time the identification of VACV-specific CD4+ T cell epitopes. By screening a large set of 15-mer peptides (2146 in total) in C57BL/6 mice, we identified 14 IAb-restricted T cell epitopes. These epitopes account for about 30% of the total anti-VACV CD4+ T cell response and are derived from 13 different structural and viral genome regulation proteins. Surprisingly, no CD4+ T cell epitopes were identified that target virulence factors. While early antigens are recognized, late antigens predominate as CD4+ T cell targets. These results are in sharp contrast to what was previously found in CD8+ T cells responses, where early antigens including virulence factors are prominently recognized. Taken together, these results highlight fundamental differences in immunodominance of CD4+ and CD8+ T cell responses to a complex pathogen and have potential implications for the development of subset vaccines. Funded by the NIH: Contract # HHSN266200400024C and RO1 grant # RO1-AI-56268. Kirin Publication Number: 837
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Morty, Rory E., Patrick Bulau, Roger Pellé, Sherwin Wilk, and Koji Abe. "Pyroglutamyl peptidase type I from Trypanosoma brucei: a new virulence factor from African trypanosomes that de-blocks regulatory peptides in the plasma of infected hosts." Biochemical Journal 394, no. 3 (February 24, 2006): 635–45. http://dx.doi.org/10.1042/bj20051593.
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Peptidases of parasitic protozoans are emerging as novel virulence factors and therapeutic targets in parasitic infections. A trypanosome-derived aminopeptidase that exclusively hydrolysed substrates with Glp (pyroglutamic acid) in P1 was purified 9248-fold from the plasma of rats infected with Trypanosoma brucei brucei. The enzyme responsible was cloned from a T. brucei brucei genomic DNA library and identified as type I PGP (pyroglutamyl peptidase), belonging to the C15 family of cysteine peptidases. We showed that PGP is expressed in all life cycle stages of T. brucei brucei and is expressed in four other blood-stream-form African trypanosomes. Trypanosome PGP was optimally active and stable at bloodstream pH, and was insensitive to host plasma cysteine peptidase inhibitors. Native purified and recombinant hyper-expressed trypanosome PGP removed the N-terminal Glp blocking groups from TRH (thyrotrophin-releasing hormone) and GnRH (gonadotropin-releasing hormone) with a kcat/Km value of 0.5 and 0.1 s−1·μM−1 respectively. The half-life of TRH and GnRH was dramatically reduced in the plasma of trypanosome-infected rats, both in vitro and in vivo. Employing an activity-neutralizing anti-trypanosome PGP antibody, and pyroglutamyl diazomethyl ketone, a specific inhibitor of type I PGP, we demonstrated that trypanosome PGP is entirely responsible for the reduced plasma half-life of TRH, and partially responsible for the reduced plasma half-life of GnRH in a rodent model of African trypanosomiasis. The abnormal degradation of TRH and GnRH, and perhaps other neuropeptides N-terminally blocked with a pyroglutamyl moiety, by trypanosome PGP, may contribute to some of the endocrine lesions observed in African trypanosomiasis.
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Reuter, Jula, Christian Otten, Nicolas Jacquier, Junghoon Lee, Dominique Mengin-Lecreulx, Iris Löckener, Robert Kluj, et al. "An NlpC/P60 protein catalyzes a key step in peptidoglycan recycling at the intersection of energy recovery, cell division and immune evasion in the intracellular pathogen Chlamydia trachomatis." PLOS Pathogens 19, no. 2 (February 2, 2023): e1011047. http://dx.doi.org/10.1371/journal.ppat.1011047.
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The obligate intracellular Chlamydiaceae do not need to resist osmotic challenges and thus lost their cell wall in the course of evolution. Nevertheless, these pathogens maintain a rudimentary peptidoglycan machinery for cell division. They build a transient peptidoglycan ring, which is remodeled during the process of cell division and degraded afterwards. Uncontrolled degradation of peptidoglycan poses risks to the chlamydial cell, as essential building blocks might get lost or trigger host immune response upon release into the host cell. Here, we provide evidence that a primordial enzyme class prevents energy intensive de novo synthesis and uncontrolled release of immunogenic peptidoglycan subunits in Chlamydia trachomatis. Our data indicate that the homolog of a Bacillus NlpC/P60 protein is widely conserved among Chlamydiales. We show that the enzyme is tailored to hydrolyze peptidoglycan-derived peptides, does not interfere with peptidoglycan precursor biosynthesis, and is targeted by cysteine protease inhibitors in vitro and in cell culture. The peptidase plays a key role in the underexplored process of chlamydial peptidoglycan recycling. Our study suggests that chlamydiae orchestrate a closed-loop system of peptidoglycan ring biosynthesis, remodeling, and recycling to support cell division and maintain long-term residence inside the host. Operating at the intersection of energy recovery, cell division and immune evasion, the peptidoglycan recycling NlpC/P60 peptidase could be a promising target for the development of drugs that combine features of classical antibiotics and anti-virulence drugs.
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Bosso, Andrea, Rosa Gaglione, Rocco Di Girolamo, Edwin J. A. Veldhuizen, Pilar García-Vello, Salvatore Fusco, Valeria Cafaro, et al. "Human Cryptic Host Defence Peptide GVF27 Exhibits Anti-Infective Properties against Biofilm Forming Members of the Burkholderia cepacia Complex." Pharmaceuticals 15, no. 2 (February 21, 2022): 260. http://dx.doi.org/10.3390/ph15020260.
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Therapeutic solutions to counter Burkholderia cepacia complex (Bcc) bacteria are challenging due to their intrinsically high level of antibiotic resistance. Bcc organisms display a variety of potential virulence factors, have a distinct lipopolysaccharide naturally implicated in antimicrobial resistance. and are able to form biofilms, which may further protect them from both host defence peptides (HDPs) and antibiotics. Here, we report the promising anti-biofilm and immunomodulatory activities of human HDP GVF27 on two of the most clinically relevant Bcc members, Burkholderia multivorans and Burkholderia cenocepacia. The effects of synthetic and labelled GVF27 were tested on B. cenocepacia and B. multivorans biofilms, at three different stages of formation, by confocal laser scanning microscopy (CLSM). Assays on bacterial cultures and on human monocytes challenged with B. cenocepacia LPS were also performed. GVF27 exerts, at different stages of formation, anti-biofilm effects towards both Bcc strains, a significant propensity to function in combination with ciprofloxacin, a relevant affinity for LPSs isolated from B. cenocepacia as well as a good propensity to mitigate the release of pro-inflammatory cytokines in human cells pre-treated with the same endotoxin. Overall, all these findings contribute to the elucidation of the main features that a good therapeutic agent directed against these extremely leathery biofilm-forming bacteria should possess.
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Liu, Mei, Xiaosai Ruan, Chengxian Zhang, Steve R. Lawson, David E. Knudsen, James P. Nataro, Donald C. Robertson, and Weiping Zhang. "Heat-Labile- and Heat-Stable-Toxoid Fusions (LTR192G-STaP13F) of Human Enterotoxigenic Escherichia coli Elicit Neutralizing Antitoxin Antibodies." Infection and Immunity 79, no. 10 (July 25, 2011): 4002–9. http://dx.doi.org/10.1128/iai.00165-11.
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ABSTRACTEnterotoxigenicEscherichia coli(ETEC) strains are a major cause of diarrheal disease in humans and animals. Adhesins and enterotoxins, including heat-labile (LT) and heat-stable (STa) toxins, are the key virulence factors. Antigenic adhesin and LT antigens have been used in developing vaccines against ETEC diarrhea. However, STa has not been included because of its poor immunogenicity and potent toxicity. Our recent study showed that porcine-type STa toxoids became immunogenic and elicited neutralizing anti-STa antibodies after being genetically fused to a full-length porcine-type LT toxoid, LTR192G(W. Zhang et al., Infect. Immun. 78:316-325, 2010). In this study, we mutated human-type LT and STa genes, which are highly homologous to porcine-type toxin genes, for a full-length LT toxoid (LTR192G) and a full-length STa toxoid (STaP13F) and genetically fused them to produce LT192-STa13toxoid fusions. Mice immunized with LT192-STa13fusion antigens developed anti-LT and anti-STa IgG (in serum and feces) and IgA antibodies (in feces). Moreover, secretory IgA antibodies from immunized mice were shown to neutralize STa and cholera toxins in T-84 cells. In addition, we fused the STa13toxoid at the N terminus and C terminus, between the A1 and A2 peptides, and between the A and B subunits of LT192to obtain different fusions in order to explore strategies for enhancing STa immunogenicity. This study demonstrated that human-type LT192-STa13fusions induce neutralizing antitoxin antibodies and provided important information for developing toxoid vaccines against human ETEC diarrhea.
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Blancas-Luciano, Blanca Esther, Ingeborg Becker-Fauser, Jaime Zamora-Chimal, José Delgado-Domínguez, Adriana Ruíz-Remigio, Elba Rosa Leyva-Huerta, Javier Portilla-Robertson, and Ana María Fernández-Presas. "Antimicrobial and anti-inflammatory activity of Cystatin C on human gingival fibroblast incubated with Porphyromonas gingivalis." PeerJ 10 (October 25, 2022): e14232. http://dx.doi.org/10.7717/peerj.14232.
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Background Periodontal disease is considered one of the most prevalent chronic infectious diseases, often leading to the disruption of tooth-supporting tissues, including alveolar bone, causing tooth mobility and loss. Porphyromonas gingivalis is considered the major etiological agent of this disease, having a plethora of virulence factors, including, lipopolysaccharides (LPS), hemolysins, and proteinases. Antimicrobial peptides are one of the main components of the innate immune response that inhibit the growth of P. gingivalis. The aim of this study was to analyze the antimicrobial activity of cystatin C and to assess the effect on the inflammatory and anti-inflammatory cytokines, the production of reactive oxygen species, and in the release of nitric oxide by human gingival fibroblasts incubated with P. gingivalis in the presence and absence of cystatin C. Methods P. gingivalis ATCC 33277 was exposed to cystatin C for 24h and co-cultured with human gingival fibroblasts (HGFs) ATCC CRL-2014. The effect of cystatin on growth of P. gingivalis and HGFs was evaluated. Pro-inflammatory (TNFα, IL-1β) and anti-inflammatory (IL-10) cytokines were determined by ELISA in the supernatants of HGFs incubated with P. gingivalis exposed to cystatin C. Additionally, nitrites and reactive oxygen species (ROS) production were evaluated. Results Cystatin Cinhibited the growth of P. gingivalis without affecting HGFs. Incubation of HGFs with P. gingivalis led to a significant increase of TNF-α and IL-1β. In contrast, HGFs incubated with P. gingivalis exposed to cystatin C showed a decreased production of both cytokines, whereas IL-10 was enhanced. Incubation of HGFs with P. gingivalis led to an increase of nitric oxide (NO) and ROS production, which was reduced in the presence of the peptide. Conclusions Cystatin C inhibits the growth of P. gingivalis and decreases the inflammatory cytokines, ROS, and NO production during infection of HGFs with P. gingivalis. Knowledge on the antimicrobial and immunomodulatory properties of cystatin C could aid in the design of new therapeutic approaches to facilitate the elimination of this bacterium to improve the treatment of periodontal disease.
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Liang, Lian-Ming, Cheng-Gang Zou, Jianping Xu, and Ke-Qin Zhang. "Signal pathways involved in microbe–nematode interactions provide new insights into the biocontrol of plant-parasitic nematodes." Philosophical Transactions of the Royal Society B: Biological Sciences 374, no. 1767 (January 14, 2019): 20180317. http://dx.doi.org/10.1098/rstb.2018.0317.
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Plant-parasitic nematodes (PPNs) cause severe damage to agricultural crops worldwide. As most chemical nematicides have negative environmental side effects, there is a pressing need for developing efficient biocontrol methods. Nematophagous microbes, the natural enemies of nematodes, are potential biocontrol agents against PPNs. These natural enemies include both bacteria and fungi and they use diverse methods to infect and kill nematodes. For instance, nematode-trapping fungi can sense host signals and produce special trapping devices to capture nematodes, whereas endo-parasitic fungi can kill nematodes by spore adhesion and invasive growth to break the nematode cuticle. By contrast, nematophagous bacteria can secrete virulence factors to kill nematodes. In addition, some bacteria can mobilize nematode-trapping fungi to kill nematodes. In response, nematodes can also sense and defend against the microbial pathogens using strategies such as producing anti-microbial peptides regulated by the innate immunity system. Recent progresses in our understanding of the signal pathways involved in microbe–nematode interactions are providing new insights in developing efficient biological control strategies against PPNs. This article is part of the theme issue ‘Biotic signalling sheds light on smart pest management'.
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Wei, Bo, Harnisha Dalwadi, Lynn K. Gordon, Carol Landers, David Bruckner, Stephan R. Targan, and Jonathan Braun. "Molecular Cloning of a Bacteroides caccaeTonB-Linked Outer Membrane Protein Identified by an Inflammatory Bowel Disease Marker Antibody." Infection and Immunity 69, no. 10 (October 1, 2001): 6044–54. http://dx.doi.org/10.1128/iai.69.10.6044-6054.2001.
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ABSTRACT Commensal enteric bacteria are a required pathogenic factor in inflammatory bowel disease (IBD), but the identity of the pertinent bacterial species is unresolved. Using an IBD-associated pANCA monoclonal antibody, a 100-kDa protein was recently characterized from an IBD clinical isolate of Bacteroides caccae (p2Lc3). In this study, consensus oligonucleotides were designed from 100-kDa peptides and used to identify a single-copy gene from the p2Lc3 genome. Sequence analysis of the genomic clone revealed a 2,844-bp (948 amino acid) open reading frame encoding features typical of the TonB-linked outer membrane protein family. This gene, termed ompW,was detected by Southern analysis only in B. caccae and was absent in other species of Bacteroides and gram-negative coliforms. The closest homologues of OmpW included the outer membrane proteins SusC of Bacteroides thetaiotaomicron and RagA of Porphyromonas gingivalis. Recombinant OmpW protein was immunoreactive with the monoclonal antibody, and serum anti-OmpW immunoglobulin A levels were elevated in a Crohn's disease patient subset. These findings suggest that OmpW may be a target of the IBD-associated immune response and reveal its structural relationship to a bacterial virulence factor of P. gingivalis and periodontal disease.
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Perng, Guey-Chuen, Barak Maguen, Ling Jin, Kevin R. Mott, John Kurylo, Lbachir BenMohamed, Ada Yukht, et al. "A Novel Herpes Simplex Virus Type 1 Transcript (AL-RNA) Antisense to the 5′ End of the Latency-Associated Transcript Produces a Protein in Infected Rabbits." Journal of Virology 76, no. 16 (August 15, 2002): 8003–10. http://dx.doi.org/10.1128/jvi.76.16.8003-8010.2002.
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ABSTRACT Following primary ocular infection, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons of the trigeminal ganglia. Latency-associated transcript (LAT), the only known viral gene abundantly transcribed during HSV-1 neuronal latency, is required for high levels of reactivation. Recently we showed that three different mutants that do not alter the LAT promoter but contain deletions within the 5′ end of the primary LAT transcript affect viral virulence (G. C. Perng et al., J. Virol. 75:9018-9028, 2001). In contrast, in LAT-null mutants viral virulence appears unaltered (T. M. Block et al., Virology 192:618-630, 1993; D. C. Bloom et al., J. Virol. 68:1283-1292, 1994; J. M. Hill et al., Virology 174:117-125, 1990; G. C. Perng et al., J. Virol. 68:8045-8055, 1994; F. Sedarati, K. M. Izumi, E. K. Wagner, and J. G. Stevens, J. Virol. 63:4455-4458, 1989). We therefore hypothesized that the 5′ end of LAT and/or an as yet unidentified gene that overlaps part of this region is involved in viral virulence. We report here on the discovery and initial characterization of a novel HSV-1 RNA consistent with such a putative gene. The novel RNA was antisense to the 5′ end of LAT and was designated AL-RNA (anti-LAT sense RNA). The AL-RNA overlapped the core LAT promoter and the first 158 nucleotides of the 5′ end of the primary LAT transcript. AL-RNA was detected in extracts from neuron-like cells (PC-12) infected with wild-type HSV-1 but not in cells infected with a mutant with the AL region deleted. The deletions in each of the above three mutants with altered virulence encompass the 5′ end of the AL-RNA, and these mutants cannot transcribe AL. This supports the hypothesis that the AL gene may play a role in viral virulence. Based on comparison to the corresponding genomic sequence, the AL-RNA did not appear to be spliced. The AL-RNA was polyadenylated and contained an open reading frame capable of encoding a protein 56 amino acids in length with a predicted molecular mass of 6.8 kDa. Sera from three of three rabbits infected with wild-type HSV-1 but not sera from any of three rabbits infected with a mutant with the AL-RNA region deleted recognized the Escherichia coli recombinantly expressed AL open reading frame on Western blots. In addition, four of six rabbits infected with wild-type virus developed enzyme-linked immunosorbent assay titers against one or more AL synthetic peptides. These results suggest that an AL protein is produced in vivo.
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Vila, Taissa, Ahmed S. Sultan, Daniel Montelongo-Jauregui, and Mary Ann Jabra-Rizk. "Oral Candidiasis: A Disease of Opportunity." Journal of Fungi 6, no. 1 (January 16, 2020): 15. http://dx.doi.org/10.3390/jof6010015.
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Oral candidiasis, commonly referred to as “thrush,” is an opportunistic fungal infection that commonly affects the oral mucosa. The main causative agent, Candida albicans, is a highly versatile commensal organism that is well adapted to its human host; however, changes in the host microenvironment can promote the transition from one of commensalism to pathogen. This transition is heavily reliant on an impressive repertoire of virulence factors, most notably cell surface adhesins, proteolytic enzymes, morphologic switching, and the development of drug resistance. In the oral cavity, the co-adhesion of C. albicans with bacteria is crucial for its persistence, and a wide range of synergistic interactions with various oral species were described to enhance colonization in the host. As a frequent colonizer of the oral mucosa, the host immune response in the oral cavity is oriented toward a more tolerogenic state and, therefore, local innate immune defenses play a central role in maintaining Candida in its commensal state. Specifically, in addition to preventing Candida adherence to epithelial cells, saliva is enriched with anti-candidal peptides, considered to be part of the host innate immunity. The T helper 17 (Th17)-type adaptive immune response is mainly involved in mucosal host defenses, controlling initial growth of Candida and inhibiting subsequent tissue invasion. Animal models, most notably the mouse model of oropharyngeal candidiasis and the rat model of denture stomatitis, are instrumental in our understanding of Candida virulence factors and the factors leading to host susceptibility to infections. Given the continuing rise in development of resistance to the limited number of traditional antifungal agents, novel therapeutic strategies are directed toward identifying bioactive compounds that target pathogenic mechanisms to prevent C. albicans transition from harmless commensal to pathogen.
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Sundarrajan, Sudarson, Junjappa Raghupatil, Aradhana Vipra, Nagalakshmi Narasimhaswamy, Sanjeev Saravanan, Chemira Appaiah, Nethravathi Poonacha, et al. "Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan." Microbiology 160, no. 10 (October 1, 2014): 2157–69. http://dx.doi.org/10.1099/mic.0.079111-0.
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P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.
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Bourgonje, A. R., S. Andreu-Sánchez, T. Vogl, S. Hu, A. Vich Vila, S. Leviatan, A. Kurilshikov, et al. "DOP53 In-depth characterisation of the serum antibody epitope repertoire in Inflammatory Bowel Disease by high-throughput phage-displayed immunoprecipitation sequencing." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i100—i102. http://dx.doi.org/10.1093/ecco-jcc/jjab232.092.
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Abstract Background Patients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome. Methods PhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C). Results Patients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn’s disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F). Conclusion This study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD.
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Linge, I. A., and A. S. Apt. "A controversial role of neutrophils in tuberculosis infection pathogenesis." Russian Journal of Infection and Immunity 11, no. 5 (August 31, 2021): 809–19. http://dx.doi.org/10.15789/2220-7619-acr-1670.
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Tuberculosis (TB) continues to be an important and unresolved medical problem. About a quarter of mankind is infected with Mycobacterium tuberculosis, and about 5–10% of these people eventually develop TB. Macrophages and CD4+ T cells are considered the key cells providing defense against TB infection. The role of neutrophils in TB is less well defined. Neutrophils are short-lived granulocytes among first migrate into the infectious lung tissue and phagocy tose mycobacteria. On the one hand, there is evidence for protective role of neutrophils in TB released via anti-microbial peptides inhibiting mycobacterial growth, up-regulation of CD4+ T-cell activation, and dendritic cell migration in the lymph nodes. On the other hand, infection of genetically TB susceptible animals leads to an overwhelming lung neutrophil inflammation, development of necrotic granulomata, and a rapid death. Neutrophils act directly or indirectly on mycobacteria by different oxidative or other reactions including neutrophil extracellular traps (NETs) formation. Phagocytosis of mycobacteria by neutrophils is accompanied by the production of pro-inflammatory factors, thus making neutrophils active participants of inflammation in all stages of the infectious process. Finally, neutrophils die by apoptosis or necrosis. Necrosis of neutrophils, which is activated by reactive oxygen species, also prolongs the inflammation. In this way, there is strong evidence that neutrophils are the cells involved in the transition of infection to the terminal stage, participating in lung tissue destruction. Although neutrophils evolutionary developed many ways to resist pathogens, it is likely, that neutrophils do not possess sufficient anti-mycobactericidal capacities due to the development of many adaptations allowing mycobacteria to survive inside the neutrophils. Neutrophils effectively phagocytose but poorly kill mycobacteria, thus hiding bacilli from more efficient killers, macrophages, and playing the role of the “Trojan Horse”. In this review, we summarize the data on the involvement of neutrophils in TB inflammation. We discuss their ambiguous role in pathogenesis which depends upon mycobacterial virulence, host genetics, dynamics of migration to inflammatory foci, and persistence during initial and chronic stages of the infectious process.
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Vahidi, Siavash, Zev A. Ripstein, Jordan B. Juravsky, Enrico Rennella, Alfred L. Goldberg, Anthony K. Mittermaier, John L. Rubinstein, and Lewis E. Kay. "An allosteric switch regulatesMycobacterium tuberculosisClpP1P2 protease function as established by cryo-EM and methyl-TROSY NMR." Proceedings of the National Academy of Sciences 117, no. 11 (March 2, 2020): 5895–906. http://dx.doi.org/10.1073/pnas.1921630117.
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The 300-kDa ClpP1P2 protease fromMycobacterium tuberculosiscollaborates with the AAA+ (ATPases associated with a variety of cellular activities) unfoldases, ClpC1 and ClpX, to degrade substrate proteins. Unlike in other bacteria, all of the components of the Clp system are essential for growth and virulence of mycobacteria, and their inhibitors show promise as antibiotics. MtClpP1P2 is unique in that it contains a pair of distinct ClpP1 and ClpP2 rings and also requires the presence of activator peptides, such as benzoyl-leucyl-leucine (Bz-LL), for function. Understanding the structural basis for this requirement has been elusive but is critical for the rational design and improvement of antituberculosis (anti-TB) therapeutics that target the Clp system. Here, we present a combined biophysical and biochemical study to explore the structure–dynamics–function relationship in MtClpP1P2. Electron cryomicroscopy (cryo-EM) structures of apo and acyldepsipeptide-bound MtClpP1P2 explain their lack of activity by showing loss of a key β-sheet in a sequence known as the handle region that is critical for the proper formation of the catalytic triad. Methyl transverse relaxation-optimized spectroscopy (TROSY)-based NMR, cryo-EM, and biochemical assays show that, on binding Bz-LL or covalent inhibitors, MtClpP1P2 undergoes a conformational change from an inactive compact state to an active extended structure that can be explained by a modified Monod–Wyman–Changeux model. Our study establishes a critical role for the handle region as an on/off switch for function and shows extensive allosteric interactions involving both intra- and interring communication that regulate MtClpP1P2 activity and that can potentially be exploited by small molecules to targetM. tuberculosis.
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Leduc, Dominique, Nathalie Beaufort, Sophie de Bentzmann, Jean-Claude Rousselle, Abdelkader Namane, Michel Chignard, and Dominique Pidard. "The Pseudomonas aeruginosa LasB Metalloproteinase Regulates the Human Urokinase-Type Plasminogen Activator Receptor through Domain-Specific Endoproteolysis." Infection and Immunity 75, no. 8 (May 21, 2007): 3848–58. http://dx.doi.org/10.1128/iai.00015-07.
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ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen in human lungs, where its secretable LasB metalloproteinase can be a virulence factor. The urokinase-type plasminogen activator receptor (uPAR) participates in pericellular proteolysis and the adherence/migration of epithelial cells and leukocytes recruited during infection and shows functional regulation by various proteinases via limited endoproteolysis occurring within its three domains (D1 to D3). We thus examined the proteolytic activity of LasB on uPAR by using recombinant uPAR as well as uPAR-expressing, human monocytic, and bronchial epithelial cell lines. Protein immunoblotting and flow immunocytometry using a panel of domain-specific anti-uPAR antibodies showed that LasB is able to cleave uPAR both within the sequence linking D1 to D2 and at the carboxy terminus of D3. Comparison of LasB-producing and LasB-deficient bacterial strains indicated that LasB is entirely responsible for the uPAR cleavage ability of P. aeruginosa. Based on amino-terminal protein microsequencing and mass spectrometry analysis of the cleavage of peptides mimicking the uPAR sequences targeted by LasB, cleavage sites were determined to be Ala84-Val85 and Thr86-Tyr87 (D1-D2) and Gln279-Tyr280 (D3). Such a dual cleavage of uPAR led to the removal of amino-terminal D1, the generation of a truncated D2D3 species, and the shedding of D2D3 from cells. This proteolytic processing of uPAR was found to (i) drastically reduce the capacity of cells to bind urokinase and (ii) abrogate the interaction between uPAR and the matrix adhesive protein vitronectin. The LasB proteinase is thus endowed with a high potential for the alteration of uPAR expression and functioning on inflammatory cells during infections by P. aeruginosa.
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Mayegowda, Shilpa Borehalli, Manjula NG, Saad Alghamdi, Banan Atwah, Zain Alhindi, and Fahadul Islam. "Role of Antimicrobial Drug in the Development of Potential Therapeutics." Evidence-Based Complementary and Alternative Medicine 2022 (May 5, 2022): 1–17. http://dx.doi.org/10.1155/2022/2500613.
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Population of the world run into several health-related emergencies among mankind and humans as it creates a challenge for the evolution of novel drug discoveries. One such can be the emergence of multidrug-resistant (MDR) strains in both hospital and community settings, which have been due to an inappropriate use and inadequate control of antibiotics that has led to the foremost human health concerns with a high impact on the global economy. So far, there has been application of two strategies for the development of anti-infective agents either by classical antibiotics that have been derived for their synthetic analogs with increased efficacy or screening natural compounds along with the synthetic compound libraries for the antimicrobial activities. However, need for newer treatment options for infectious diseases has led research to develop new generation of antimicrobial activity to further lessen the spread of antibiotic resistance. Currently, the principles aim to find novel mode of actions or products to target the specific sites and virulence factors in pathogens by a series of better understanding of physiology and molecular aspects of the microbial resistance, mechanism of infection process, and gene-pathogenicity relationship. The design various novel strategies tends to provide us a path for the development of various antimicrobial therapies that intends to have a broader and wider antimicrobial spectrum that helps to combat MDR strains worldwide. The development of antimicrobial peptides, metabolites derived from plants, microbes, phage-based antimicrobial agents, use of metal nanoparticles, and role of CRISPR have led to an exceptional strategies in designing and developing the next-generation antimicrobials. These novel strategies might help to combat the seriousness of the infection rates and control the health crisis system.
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Riley, E. M. "The role of MHC- and non-MHC-associated genes in determining the human immune response to malaria antigens." Parasitology 112, S1 (March 1996): S39—S51. http://dx.doi.org/10.1017/s0031182000076654.
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SUMMARYIndividual susceptibility to malaria infection, disease and death is influenced by host genotype, parasite virulence and a number of environmental factors including malaria-specific immunity. Immune responses are themselves determined by a combination of host genes and environmental effects. The extent to which host genotype limits the spectrum of possible immune responses may influence the outcome of infection and has consequences for vaccine design. Associations have been observed between human major histocompatibility complex (MHC) genotype and susceptibility to severe malaria, but no similar associations have been observed for mild malarial disease or for specific antibody responses to defined malaria antigens. Epidemiological studies have shown that, in practice, neither T helper cell nor antibody responses to malaria parasites are limited by host MHC genotype, but have revealed that genes lying outside the MHC may influence T cell proliferative responses. These genes have yet to be identified, but possible candidates include T cell receptor (TcR) genes, and genes involved in TcR gene rearrangements. More importantly, perhaps, longitudinal epidemiological studies have shown that the anti-malarial antibody repertoire is selective and becomes fixed in malaria-immune individuals, but is independent of host genotype. These findings suggest that the antibody repertoire may be determined, at least in part, by stochastic events. The first of these is the generation of the T and B cell repertoire, which results from random gene recombinations and somatic mutation and is thus partially independent of germline genes. Secondly, of the profusion of immunogenic peptides which are processed and presented by antigen presenting cells, a few will, by chance, interact with T and B cell surface antigen receptors of particularly high affinity. These T and B cell clones will be selected, will expand and may come to dominate the immune response, preventing the recognition of variant epitopes presented by subsequent infections - a process known as original antigenic sin or clonal imprinting. The immune response of an individual thus reflects the balance between genetic and stochastic effects. This may have important consequences for subunit vaccine development.
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Jafari, Paris, Alexandre Luscher, Thissa Siriwardena, Murielle Michetti, Yok-Ai Que, Laurence G. Rahme, Jean-Louis Reymond, et al. "Antimicrobial Peptide Dendrimers and Quorum-Sensing Inhibitors in Formulating Next-Generation Anti-Infection Cell Therapy Dressings for Burns." Molecules 26, no. 13 (June 24, 2021): 3839. http://dx.doi.org/10.3390/molecules26133839.
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Multidrug resistance infections are the main cause of failure in the pro-regenerative cell-mediated therapy of burn wounds. The collagen-based matrices for delivery of cells could be potential substrates to support bacterial growth and subsequent lysis of the collagen leading to a cell therapy loss. In this article, we report the development of a new generation of cell therapy formulations with the capacity to resist infections through the bactericidal effect of antimicrobial peptide dendrimers and the anti-virulence effect of anti-quorum sensing MvfR (PqsR) system compounds, which are incorporated into their formulation. Anti-quorum sensing compounds limit the pathogenicity and antibiotic tolerance of pathogenic bacteria involved in the burn wound infections, by inhibiting their virulence pathways. For the first time, we report a biological cell therapy dressing incorporating live progenitor cells, antimicrobial peptide dendrimers, and anti-MvfR compounds, which exhibit bactericidal and anti-virulence properties without compromising the viability of the progenitor cells.
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Linz, Bodo, Irshad Sharafutdinov, Nicole Tegtmeyer, and Steffen Backert. "Evolution and Role of Proteases in Campylobacter jejuni Lifestyle and Pathogenesis." Biomolecules 13, no. 2 (February 8, 2023): 323. http://dx.doi.org/10.3390/biom13020323.
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Infection with the main human food-borne pathogen Campylobacter jejuni causes campylobacteriosis that accounts for a substantial percentage of gastrointestinal infections. The disease usually manifests as diarrhea that lasts for up to two weeks. C. jejuni possesses an array of peptidases and proteases that are critical for its lifestyle and pathogenesis. These include serine proteases Cj1365c, Cj0511 and HtrA; AAA+ group proteases ClpP, Lon and FtsH; and zinc-dependent protease PqqE, proline aminopeptidase PepP, oligopeptidase PepF and peptidase C26. Here, we review the numerous critical roles of these peptide bond-dissolving enzymes in cellular processes of C. jejuni that include protein quality control; protein transport across the inner and outer membranes into the periplasm, cell surface or extracellular space; acquisition of amino acids and biofilm formation and dispersal. In addition, we highlight their role as virulence factors that inflict intestinal tissue damage by promoting cell invasion and mediating cleavage of crucial host cell factors such as epithelial cell junction proteins. Furthermore, we reconstruct the evolution of these proteases in 34 species of the Campylobacter genus. Finally, we discuss to what extent C. jejuni proteases have initiated the search for inhibitor compounds as prospective novel anti-bacterial therapies.
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Michael-Gayego, Ayelet, Mary Dan-Goor, Joseph Jaffe, Carlos Hidalgo-Grass, and Allon E. Moses. "Characterization ofsilin Invasive Group A and G Streptococci: Antibodies against Bacterial Pheromone Peptide SilCR Result in Severe Infection." Infection and Immunity 81, no. 11 (August 26, 2013): 4121–27. http://dx.doi.org/10.1128/iai.00359-13.
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ABSTRACTGroup G beta-hemolytic streptococcus (GGS) strains cause severe invasive infections, mostly in patients with comorbidities. GGS is known to possess virulence factors similar to those of its more virulent counterpart group A streptococcus (GAS). A streptococcal invasion locus,sil, was identified in GAS.silencodes a competence-stimulating peptide named SilCR that activates bacterial quorum sensing and has the ability to attenuate virulence in GAS infections. We found thatsilis present in most GGS strains (82%) but in only 25% of GAS strains, with a similar gene arrangement. GGS strains that containedsilexpressed the SilCR peptide and secreted it into the growth medium. In a modified murine model of GGS soft tissue infection, GGS grown in the presence of SilCR caused a milder disease than GGS grown in the absence of SilCR. To further study the role of the peptide in bacterial virulence attenuation, we vaccinated mice with SilCR to produce specific anti-SilCR antibodies. Vaccinated mice developed a significantly more severe illness than nonvaccinated mice. Our results indicate that thesillocus is much more prevalent among the less virulent GGS strains than among GAS strains. GGS strains express and secrete SilCR, which has a role in attenuation of virulence in a murine model. We show that the SilCR peptide can protect mice from infection caused by GGS. Furthermore, vaccinated mice that produce specific anti-SilCR antibodies develop a significantly more severe infection. To our knowledge, this is a novel report demonstrating that specific antibodies against a bacterial component cause more severe infection by those bacteria.
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Gutierrez-Gongora, Davier, and Jennifer Geddes-McAlister. "Peptidases: promising antifungal targets of the human fungal pathogen, Cryptococcus neoformans." FACETS 7 (January 1, 2022): 319–42. http://dx.doi.org/10.1139/facets-2021-0157.
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Cryptococcus neoformans is a globally important fungal pathogen, primarily inflicting disease on immunocompromised individuals. The widespread use of antifungal agents in medicine and agriculture supports the development of antifungal resistance through evolution, and the emergence of new strains with intrinsic resistance drives the need for new therapeutics. For C. neoformans, the production of virulence factors, including extracellular peptidases (e.g., CnMpr-1 and May1) with mechanistic roles in tissue invasion and fungal survival, constitute approximately 2% of the fungal proteome and cover five classes of enzymes. Given their role in fungal virulence, peptidases represent promising targets for anti-virulence discovery in the development of new approaches against C. neoformans. Additionally, intracellular peptidases, which are involved in resistance mechanisms against current treatment options (e.g., azole drugs), as well as capsule biosynthesis and elaboration of virulence factors, present additional opportunities to combat the pathogen. In this review, we highlight key cryptococcal peptidases with defined or predicted roles in fungal virulence and assess sequence alignments against their human homologs. With this information, we define the feasibility of the select peptidases as “druggable” targets for inhibition, representing prospective therapeutic options against the deadly fungus.
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Herrera, Andrea L., and Michael S. Chaussee. "Signaling Peptide SpoV Is Essential for Streptococcus pyogenes Virulence, and Prophylaxis with Anti-SpoV Decreases Disease Severity." Microorganisms 9, no. 11 (November 10, 2021): 2321. http://dx.doi.org/10.3390/microorganisms9112321.
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Streptococcal peptide of virulence (SpoV) is a Streptococcus pyogenes (group A streptococcus (GAS))-specific peptide that is important for GAS survival in murine blood, and the expression of the virulence factors streptolysin O (slo) and streptolysin S (sagA). We used a spoV mutant in isolate MGAS315 to assess the contribution of the SpoV peptide to virulence by using a murine model of invasive disease and an ex vivo human model (Lancefield assay). We then used antibodies to SpoV in both models to evaluate their ability to decrease morbidity and mortality. Results showed that SpoV is essential for GAS virulence, and targeting the peptide has therapeutic potential.
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Desouky, Said E., Mohammed Abu-Elghait, Eman A. Fayed, Samy Selim, Basit Yousuf, Yasuhiro Igarashi, Basel A. Abdel-Wahab, Amnah Mohammed Alsuhaibani, Kenji Sonomoto, and Jiro Nakayama. "Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study." Metabolites 12, no. 3 (March 15, 2022): 246. http://dx.doi.org/10.3390/metabo12030246.
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Anti-virulence agents are non-bacteriostatic and non-bactericidal emerging therapeutic options which hamper the production of virulence factors in pathogenic flora. In Staphylococcus aureus and Enterococcus faecalis, regulation of virulence genes’ expression occurs through the cyclic peptide-mediated accessory gene regulator (agr) and its ortholog fsr quorum sensing systems, respectively. In the present study, we screened a set of 54 actinomycetales secondary metabolites as novel anti-virulence compounds targeting quorum sensing system of the Gram-positive bacteria. The results indicated that four compounds, Phenalinolactones A–D, BU–4664LMe, 4,5-dehydrogeldamycin, and Questinomycin A, potentially inhibit the agr quorum sensing system and hemolytic activity of S. aureus. On the other hand, Decatromicin A and B, Okilactomycin, Rishirilide A, Abyssomicin I, and Rebeccamycin selectively blocked the fsr quorum sensing system and the gelatinase production in E. faecalis at sub-lethal concentrations. Interestingly, Synerazol uniquely showed the capability to inhibit both fsr and agr quorum sensing systems. Further, in silico molecular docking studies were performed which provided closer insights into the mode of action of these compounds and proposed that the inhibitory activity of these compounds could be attributed to their potential ability to bind to the ATP-active site of S. aureus AgrA. Taken together, our study highlights the potential of actinomycetales secondary metabolites with diverse structures as anti-virulence quorum sensing inhibitors.
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Cwiklinski, Krystyna, and John Pius Dalton. "Exploiting Comparative Omics to Understand the Pathogenic and Virulence-Associated Protease: Anti-Protease Relationships in the Zoonotic Parasites Fasciola hepatica and Fasciola gigantica." Genes 13, no. 10 (October 14, 2022): 1854. http://dx.doi.org/10.3390/genes13101854.
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The helminth parasites, Fasciola hepatica and Fasciola gigantica, are the causative agents of fasciolosis, a global and economically important disease of people and their livestock. Proteases are pivotal to an array of biological processes related to parasitism (development, feeding, immune evasion, virulence) and therefore their action requires strict regulation by parasite anti-proteases (protease inhibitors). By interrogating the current publicly available Fasciola spp. large sequencing datasets, including several genome assemblies and life cycle stage-specific transcriptome and proteome datasets, we reveal the complex profile and structure of proteases and anti-proteases families operating at various stages of the parasite’s life cycle. Moreover, we have discovered distinct profiles of peptidases and their cognate inhibitors expressed by the parasite stages in the intermediate snail host, reflecting the different environmental niches in which they move, develop and extract nutrients. Comparative genomics revealed a similar cohort of peptidase inhibitors in F. hepatica and F. gigantica but a surprisingly reduced number of cathepsin peptidases genes in the F. gigantica genome assemblies. Chromosomal location of the F. gigantica genes provides new insights into the evolution of these gene families, and critical data for the future analysis and interrogation of Fasciola spp. hybrids spreading throughout the Asian and African continents.