Journal articles on the topic 'Antimicrobial PEPTIDES IN VIVO'
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Bals, Robert, Daniel J. Weiner, A. David Moscioni, Rupalie L. Meegalla, and James M. Wilson. "Augmentation of Innate Host Defense by Expression of a Cathelicidin Antimicrobial Peptide." Infection and Immunity 67, no. 11 (November 1, 1999): 6084–89. http://dx.doi.org/10.1128/iai.67.11.6084-6089.1999.
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ABSTRACT Antimicrobial peptides, such as defensins or cathelicidins, are effector substances of the innate immune system and are thought to have antimicrobial properties that contribute to host defense. The evidence that vertebrate antimicrobial peptides contribute to innate immunity in vivo is based on their expression pattern and in vitro activity against microorganisms. The goal of this study was to investigate whether the overexpression of an antimicrobial peptide results in augmented protection against bacterial infection. C57BL/6 mice were given an adenovirus vector containing the cDNA for LL-37/hCAP-18, a human cathelicidin antimicrobial peptide. Mice treated with intratracheal LL-37/hCAP-18 vector had a lower bacterial load and a smaller inflammatory response than did untreated mice following pulmonary challenge with Pseudomonas aeruginosa PAO1. Systemic expression of LL-37/hCAP-18 after intravenous injection of recombinant adenovirus resulted in improved survival rates following intravenous injection of lipopolysaccharide with galactosamine or Escherichia coli CP9. In conclusion, the data demonstrate that expression of an antimicrobial peptide by gene transfer results in augmentation of the innate immune response, providing support for the hypothesis that vertebrate antimicrobial peptides protect against microorganisms in vivo.
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Schouten, Gina, Felix Paulussen, Oscar Kuipers, Wilbert Bitter, Tom Grossmann, and Peter van Ulsen. "Stapling of Peptides Potentiates the Antibiotic Treatment of Acinetobacter baumannii In Vivo." Antibiotics 11, no. 2 (February 19, 2022): 273. http://dx.doi.org/10.3390/antibiotics11020273.
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The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.
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Kopeykin, P. M., M. S. Sukhareva, N. V. Lugovkina, and O. V. Shamova. "CHEMICAL SYNTHESIS AND ANALYSIS OF ANTIMICROBIAL AND HEMOLYTIC ACTIVITY OF STRUCTURAL ANALOGOUS OF A PEPTIDE PROTEGRIN 1." Medical academic journal 19, no. 1S (December 15, 2019): 169–70. http://dx.doi.org/10.17816/maj191s1169-170.
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Search for new tools for combating infectious diseases and investigation of molecular mechanisms of their antimicrobial action in in vitro and in vivo models are the urgent tasks of experimental medicine and pathophysiology. A promising direction for the development of new effective antibiotic drugs is creation of analogues of natural protective molecules that provide a host defense against pathogenic bacteria, in particular analogues of antimicrobial peptides of the innate immune system. The aim of our work was design, chemical synthesis and characterization of antimicrobial and hemolytic activity of a peptide protegrin 1 (PG1) structural variants. Three analogues of PG1 were produced and studied, it was shown that two PG1 variants exhibit a high activity against antibiotic-resistant bacteria. A comparative analysis of the hemolytic activity of the peptides towards human erythrocytes was carried out. The ways of further work directed to creation of novel antimicrobials based on a natural peptide PG1 for combating drug-resistant bacteria are outlined.
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Hu, Alvin. "Conjugation of Silver Nanoparticles With De Novo–Engineered Cationic Antimicrobial Peptides: Exploratory Proposal." JMIR Research Protocols 10, no. 12 (December 8, 2021): e28307. http://dx.doi.org/10.2196/28307.
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Background Cationic antimicrobial peptides have broad antimicrobial activity and provide a novel way of targeting multidrug-resistant bacteria in the era of increasing antimicrobial resistance. Current developments show positive prospects for antimicrobial peptides and silver nanoparticles (AgNPs) individually. Objective The primary objective is to propose another method for enhancing antimicrobial activity by conjugating AgNPs with cationic antimicrobial peptides, with a subsequent preliminary assessment of the minimum inhibitory concentration of multidrug-resistant bacteria. The secondary objective is to evaluate the safety of the conjugated compound and assess its viability for in vivo use. Methods The proposal involves 3 stages. First, WLBU2C, a modified version of the antimicrobial peptide WLBU2 with an added cysteine group, needs to be synthesized using a standard Fmoc procedure. It can then be stably conjugated with AgNPs ideally through photochemical means. Second, the WLBU2C-AgNP conjugate should be tested for antimicrobial activity according to the Clinical & Laboratory Standards Institute manual on standard minimum inhibitory concentration testing. Third, the cytotoxicity of the conjugate should be tested using cell lysis assays if the above stages are completed. Results I-TASSER (iterative threading assembly refinement) simulation revealed that the modified peptide WLBU2C has a secondary structure similar to that of the original WLBU2 peptide. No other results have been obtained at this time. Conclusions The addition of AgNPs to already developed de novo–engineered antimicrobial peptides provides an opportunity for the development of potent antimicrobials. Future prospects include emergency last-line therapy and treatment for current difficult-to-eradicate bacterial colonization, such as in cystic fibrosis, implantable medical devices, cancer, and immunotherapy. As I do not anticipate funding at this time, I hope this proposal provides inspiration to other researchers. International Registered Report Identifier (IRRID) PRR1-10.2196/28307
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Moser, Christian, Daniel J. Weiner, Elena Lysenko, Robert Bals, Jeffrey N. Weiser, and James M. Wilson. "β-Defensin 1 Contributes to Pulmonary Innate Immunity in Mice." Infection and Immunity 70, no. 6 (June 2002): 3068–72. http://dx.doi.org/10.1128/iai.70.6.3068-3072.2002.
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ABSTRACT Innate immunity serves as a first line defense in vertebrate organisms by providing an initial barrier to microorganisms and triggering antigen-specific responses. Antimicrobial peptides are thought to be effectors of innate immunity through their antibiotic activity and direct killing of microorganisms. Evidence to support this hypothesis in vertebrates is indirect, based on expression profiles and in vitro assays using purified peptides. Here we investigated the function of antimicrobial peptides in vivo using mice deficient in an antimicrobial peptide, mouse β-defensin-1 (mBD-1). We find that loss of mBD-1 results in delayed clearance of Haemophilus influenzae from lung. These data demonstrate directly that antimicrobial peptides of vertebrates provide an initial block to bacteria at epithelial surfaces.
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Yeaman, Michael R., Kimberly D. Gank, Arnold S. Bayer, and Eric P. Brass. "Synthetic Peptides That Exert Antimicrobial Activities in Whole Blood and Blood-Derived Matrices." Antimicrobial Agents and Chemotherapy 46, no. 12 (December 2002): 3883–91. http://dx.doi.org/10.1128/aac.46.12.3883-3891.2002.
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ABSTRACT Peptides that exert antimicrobial activity in artificial media may lack activity within blood or other complex biological matrices. To facilitate the evaluation of antimicrobial peptides for possible therapeutic utility, an ex vivo assay was developed to assess the extent and durability of peptide antimicrobial activities in complex fluid biomatrices of whole blood, plasma, and serum compared with those in conventional media. Novel antimicrobial peptides (RP-1 and RP-11) were designed based in part on platelet microbicidal proteins. RP-1, RP-11, or gentamicin was introduced into biomatrices either coincident with, or 2 h prior to, inoculation with an Escherichia coli target organism. Antimicrobial activities of peptides were assessed by quantitative culture 2 h after bacterial inoculation and compared to those of peptide-free and gentamicin controls. In whole blood and homologous plasma or serum, introduction of RP-1 or RP-11 coincident with E. coli was associated with a significant reduction in CFU per milliliter versus the respective peptide-free controls. Moreover, substantial antimicrobial activity remained when RP-1 or RP-11 was placed into whole blood or plasma 2 h prior to E. coli inoculation. These results suggest that the peptides were not rapidly inactivated within these biomatrices. Peptide antimicrobial activities were negatively affected by preincubation in serum or in heat-inactivated serum, compared with those of the respective controls. Peptides RP-1 and RP-11 were consistently effective at lower concentrations in biomatrices than in artificial media, indicating favorable antimicrobial interactions with components of blood or blood fractions. Collectively, these findings support the concept that synthetic peptides can be designed to exert potent antimicrobial activities in relevant and complex biological matrices.
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Bhargavi Ram, Thimmiah, Chien Chien Belinda Tang, Siaw Fui Kiew, Sie Yon Lau, Gobi Gobi, Jeevanandam Jaison, and Michael K. Danquah. "Nanoformulation of Peptides for Pharmaceutical Applications: In Vitro and In Vivo Perspectives." Applied Sciences 12, no. 24 (December 13, 2022): 12777. http://dx.doi.org/10.3390/app122412777.
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Peptides are short sequences of proteins consisting of two or more amino acids that are linked by peptide bonds. Peptide-based designs and drug deliveries can offer several advantages, such as antioxidant, antimicrobial, antihypertensive activities, along with immunomodulatory and antithrombotic properties, with hormone or drug-like potential. Peptide-based therapeutic formulations are used as drug candidates for the treatment of various diseases. However, there are several concerns associated with the efficacy of peptides in pharmaceutical design and delivery, including rapid degradation, limited solubility, and poor permeability. The nanoformulation of peptides has been identified as a promising approach for improving the stability of peptides and providing metabolic stability and bioavailability. This article provides an overview of the advances in the development of peptides for drug design and formulation applications. It discusses various peptide nanoformulation approaches as well as recent developments in the in vitro and in vivo analyses of nanoformulated peptides for pharmaceutical applications.
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Boullet, Héloise, Fayçal Bentot, Arnaud Hequet, Carine Ganem-Elbaz, Chérine Bechara, Emeline Pacreau, Pierre Launay, et al. "Small AntiMicrobial Peptide with In Vivo Activity Against Sepsis." Molecules 24, no. 9 (May 1, 2019): 1702. http://dx.doi.org/10.3390/molecules24091702.
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Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic -amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice.
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Zhang, Lijuan, Jody Parente, Scott M. Harris, Donald E. Woods, Robert E. W. Hancock, and Timothy J. Falla. "Antimicrobial Peptide Therapeutics for Cystic Fibrosis." Antimicrobial Agents and Chemotherapy 49, no. 7 (July 2005): 2921–27. http://dx.doi.org/10.1128/aac.49.7.2921-2927.2005.
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ABSTRACT Greater than 90% of lung infections in cystic fibrosis (CF) patients are caused by Pseudomonas aeruginosa, and the majority of these patients subsequently die from lung damage. Current therapies are either targeted at reducing obstruction, reducing inflammation, or reducing infection. To identify potential therapeutic agents for the CF lung, 150 antimicrobial peptides consisting of three distinct structural classes were screened against mucoid and multidrug-resistant clinical isolates of P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus. Five peptides that retained potent antimicrobial activities in physiological salt and divalent cation environment were further characterized in vivo using a rat chronic lung infection model. All animals were inoculated intratracheally with 104 P. aeruginosa mucoid PAO1 cells in agar beads. Three days following inoculation treatment was initiated. Animals were treated daily for 3 days with 100 μl of peptide solution (1 mg/ml) in 10 mM sodium citrate, which was deposited via either intratracheal instillation or aerosolization. Control animals received daily exposure to vehicle alone. At the end of the treatment the lungs of the animals were removed for quantitative culture. Four peptides, HBCM2, HBCM3, HBCPα-2, and HB71, demonstrated significant reduction in Pseudomonas bioburden in the lung of rats. Further in vivo studies provided direct evidence that anti-inflammatory activity was associated with three of these peptides. Therefore, small bioactive peptides have the potential to attack two of the components responsible for the progression of lung damage in the CF disease: infection and inflammation.
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Rodrigues, Elaine G., Andrey S. Dobroff, Carlos P. Taborda, and Luiz R. Travassos. "Antifungal and antitumor models of bioactive protective peptides." Anais da Academia Brasileira de Ciências 81, no. 3 (September 2009): 503–20. http://dx.doi.org/10.1590/s0001-37652009000300015.
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Peptides are remarkably reactive molecules produced by a great variety of species and able to display a number of functions in uni-and multicellular organisms as mediators, agonists and regulating substances. Some of them exert cytotoxic effects on cells other than those that produced them, and may have a role in controlling subpopulations and protecting certain species or cell types. Presently, we focus on antifungal and antitumor peptides and discuss a few models in which specific sequences and structures exerted direct inhibitory effects or stimulated a protective immune response. The killer peptide, deduced from an antiidiotypic antibody, with several antimicrobial activities and other Ig-derived peptides with cytotoxic activities including antitumor effects, are models studied in vitro and in vivo. Peptide 10 from gp43 of P. brasiliensis (P10) and the vaccine perspective against paracoccidioidomycosis is another topic illustrating the protective effect in vivo against a pathogenic fungus. The cationic antimicrobial peptides with antitumor activities are mostly reviewed here. Local treatment of murine melanoma by the peptide gomesin is another model studied at the Experimental Oncology Unit of UNIFESP.
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Scorzoni, Liliana, Ana Carolina Alves de Paula e Silva, Haroldo Cesar de Oliveira, Claudia Tavares dos Santos, Junya de Lacorte Singulani, Patricia Akemi Assato, Caroline Maria Marcos, et al. "In Vitro and In Vivo Effect of Peptides Derived from 14-3-3 Paracoccidioides spp. Protein." Journal of Fungi 7, no. 1 (January 13, 2021): 52. http://dx.doi.org/10.3390/jof7010052.
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Background: Paracoccidioidomycosis (PCM) is a chronic disease that causes sequelae and requires prolonged treatment; therefore, new therapeutic approaches are necessary. In view of this, three peptides from Paracoccidioides brasiliensis 14-3-3 protein were selected based on its immunogenicity and therapeutic potential. Methods: The in vitro antifungal activity and cytotoxicity of the 14-3-3 peptides were evaluated. The influence of the peptides in immunological and survival aspects was evaluated in vivo, using Galleria mellonella and the expression of antimicrobial peptide genes in Caenorhabditis elegans. Results: None of the peptides were toxic to HaCaT (skin keratinocyte), MRC-5 (lung fibroblast), and A549 (pneumocyte) cell lines, and only P1 exhibited antifungal activity against Paracoccidioides spp. The peptides could induce an immune response in G. mellonella. Moreover, the peptides caused a delay in the death of Paracoccidioides spp. infected larvae. Regarding C. elegans, the three peptides were able to increase the expression of the antimicrobial peptides. These peptides had essential effects on different aspects of Paracoccidioides spp. infection showing potential for a therapeutic vaccine. Future studies using mammalian methods are necessary to validate our findings.
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Hitt, Samantha J., Barney M. Bishop, and Monique L. van Hoek. "Komodo-dragon cathelicidin-inspired peptides are antibacterial against carbapenem-resistant Klebsiella pneumoniae." Journal of Medical Microbiology 69, no. 11 (November 1, 2020): 1262–72. http://dx.doi.org/10.1099/jmm.0.001260.
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Introduction. The rise of carbapenem-resistant enterobacteriaceae (CRE) is a growing crisis that requires development of novel therapeutics. Hypothesis. To this end, cationic antimicrobial peptides (CAMPs) represent a possible source of new potential therapeutics to treat difficult pathogens such as carbapenem-resistant Klebsiella pneumoniae (CRKP), which has gained resistance to many if not all currently approved antibiotics, making treatment difficult. Aim. To examine the anti-CRKP antimicrobial activity of the predicted cathelicidins derived from Varanus komodoensis (Komodo dragon) as well as synthetic antimicrobial peptides that we created. Methodology. We determined the minimum inhibitory concentrations of the peptides against CRKP. We also characterized the abilities of these peptides to disrupt the hyperpolarization of the bacterial membrane as well as their ability to form pores in the membrane. Results. We did not observe significant anti-CRKP activity for the predicted native Komodo cathelicidin peptides. We found that the novel peptides DRGN-6,-7 and -8 displayed significant antimicrobial activity against CRKP with MICs of 4–8 µg ml−1. DRGN-6 peptide was the most effective peptide against CRKP. Unfortunately, these peptides showed higher than desired levels of hemolysis, although in vivo testing in the waxworm Galleria mellonella showed no mortality associated with treatment by the peptide; however, CRKP-infected waxworms treated with peptide did not show an improvement in survival. Conclusion. Given the challenges of treating CRKP, identification of peptides with activity against it represents a promising avenue for further research. Given DRGN-6′s similar level of activity to colistin, DRGN-6 is a promising template for the development of novel antimicrobial peptide-based therapeutics.
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Li, Jiarui, Guillem Prats-Ejarque, Marc Torrent, David Andreu, Klaus Brandenburg, Pablo Fernández-Millán, and Ester Boix. "In Vivo Evaluation of ECP Peptide Analogues for the Treatment of Acinetobacter baumannii Infection." Biomedicines 10, no. 2 (February 5, 2022): 386. http://dx.doi.org/10.3390/biomedicines10020386.
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Antimicrobial peptides (AMPs) are alternative therapeutics to traditional antibiotics against bacterial resistance. Our previous work identified an antimicrobial region at the N-terminus of the eosinophil cationic protein (ECP). Following structure-based analysis, a 30mer peptide (ECPep-L) was designed that combines antimicrobial action against Gram-negative species with lipopolysaccharides (LPS) binding and endotoxin-neutralization activities. Next, analogues that contain non-natural amino acids were designed to increase serum stability. Here, two analogues were selected for in vivo assays: the all-D version (ECPep-D) and the Arg to Orn version that incorporates a D-amino acid at position 2 (ECPep-2D-Orn). The peptide analogues retained high LPS-binding and anti-endotoxin activities. The peptides efficacy was tested in a murine acute infection model of Acinetobacter baumannii. Results highlighted a survival rate above 70% following a 3-day supervision with a single administration of ECPep-D. Moreover, in both ECPep-D and ECPep-2D-Orn peptide-treated groups, clinical symptoms improved significantly and the tissue infection was reduced to equivalent levels to mice treated with colistin, used as a last resort in the clinics. Moreover, treatment drastically reduced serum levels of TNF-α inflammation marker within the first 8 h. The present results support ECP-derived peptides as alternative candidates for the treatment of acute infections caused by Gram-negative bacteria.
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Jia, X., A. Patrzykat, R. H. Devlin, P. A. Ackerman, G. K. Iwama, and R. E. W. Hancock. "Antimicrobial Peptides Protect Coho Salmon fromVibrio anguillarum Infections." Applied and Environmental Microbiology 66, no. 5 (May 1, 2000): 1928–32. http://dx.doi.org/10.1128/aem.66.5.1928-1932.2000.
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ABSTRACT Fish losses from infectious diseases are a significant problem in aquaculture worldwide. Therefore, we investigated the ability of cationic antimicrobial peptides to protect against infection caused by the fish pathogen Vibrio anguillarum. To identify effective peptides for fish, the MICs of certain antimicrobial peptides against fish pathogens were determined in vitro. Two of the most effective antimicrobial peptides, CEME, a cecropin-melittin hybrid peptide, and pleurocidin amide, a C-terminally amidated form of the natural flounder peptide, were selected for in vivo studies. A single intraperitoneal injection of CEME did not affect mortality rates in juvenile coho salmon infected with V. anguillarum, the causative agent of vibriosis. Therefore, the peptides were delivered continuously using miniosmotic pumps placed in the peritoneal cavity. Twelve days after pump implantation, the fish received intraperitoneal injections ofV. anguillarum at a dose that would kill 50 to 90% of the population. Fish receiving 200 μg of CEME per day survived longer and had significantly lower accumulated mortalities (13%) than the control groups (50 to 58%). Fish receiving pleurocidin amide at 250 μg per day also survived longer and had significantly lower accumulated mortalities (5%) than the control groups (67 to 75%). This clearly shows the potential for antimicrobial peptides to protect fish against infections and indicates that the strategy of overexpressing the peptides in transgenic fish may provide a method of decreasing bacterial disease problems.
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Eriksson, Olaspers Sara, Miriam Geörg, Hong Sjölinder, Rannar Sillard, Staffan Lindberg, Ülo Langel, and Ann-Beth Jonsson. "Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection." Antimicrobial Agents and Chemotherapy 57, no. 8 (May 20, 2013): 3704–12. http://dx.doi.org/10.1128/aac.00624-13.
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ABSTRACTMeningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action againstNeisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activityin vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected withN. meningitidisas well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activityin vivo, indicates the possibility to design peptide-based therapies for infectious diseases.
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Zhang, Wenxu, Jiangcheng He, Junchen Wu, and Carsten Schmuck. "In Vivo Detoxification of Lipopolysaccharide by Antimicrobial Peptides." Bioconjugate Chemistry 28, no. 2 (December 20, 2016): 319–24. http://dx.doi.org/10.1021/acs.bioconjchem.6b00664.
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Neff, Jennifer A., Danir F. Bayramov, Esha A. Patel, and Jing Miao. "Novel Antimicrobial Peptides Formulated in Chitosan Matrices are Effective Against Biofilms of Multidrug-Resistant Wound Pathogens." Military Medicine 185, Supplement_1 (January 2020): 637–43. http://dx.doi.org/10.1093/milmed/usz222.
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ABSTRACT Introduction Infection frequently complicates the treatment of combat-related wounds, impairs healing, and leads to worse outcomes. To better manage wound infections, antimicrobial therapies that are effective against biofilm and designed for direct wound application are needed. The primary objective of this work was to evaluate a chitosan matrix for delivery of two engineered antimicrobial peptides, (ASP)-1 and ASP-2, to treat biofilm-associated bacteria. A secondary objective was to determine whether replacing the levorotatory (L) form amino acids in ASP-2 with dextrorotatory (D) form amino acids would impact peptide activity. Materials and Methods Chitosan gels loaded with antimicrobial peptides were evaluated for peptide release over 7 days and tested for efficacy against biofilms grown both in vitro on polymer mesh and ex vivo on porcine skin. Results When delivered via chitosan, 70% to 80% of peptides were released over 7 days. Gels eradicated biofilms of gram-positive and gram-negative, drug-resistant bacteria in vitro and ex vivo. Under the conditions tested, no meaningful differences in peptide activity between the L and D forms of ASP-2 were detected. Conclusions Chitosan serves as an effective delivery platform for ASP-1 and ASP-2 to treat biofilm-embedded bacteria and warrants further development as a topical treatment.
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Mishra, Biswajit, Jayaram Lakshmaiah Narayana, Tamara Lushnikova, Xiuqing Wang, and Guangshun Wang. "Low cationicity is important for systemic in vivo efficacy of database-derived peptides against drug-resistant Gram-positive pathogens." Proceedings of the National Academy of Sciences 116, no. 27 (June 17, 2019): 13517–22. http://dx.doi.org/10.1073/pnas.1821410116.
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As bacterial resistance to traditional antibiotics continues to emerge, new alternatives are urgently needed. Antimicrobial peptides (AMPs) are important candidates. However, how AMPs are designed with in vivo efficacy is poorly understood. Our study was designed to understand structural moieties of cationic peptides that would lead to their successful use as antibacterial agents. In contrast to the common perception, serum binding and peptide stability were not the major reasons for in vivo failure in our studies. Rather, our systematic study of a series of peptides with varying lysines revealed the significance of low cationicity for systemic in vivo efficacy against Gram-positive pathogens. We propose that peptides with biased amino acid compositions are not favored to associate with multiple host factors and are more likely to show in vivo efficacy. Thus, our results uncover a useful design strategy for developing potent peptides against multidrug-resistant pathogens.
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Kim, Byoungkwan, Susan M. Richards, John S. Gunn, and James M. Slauch. "Protecting against Antimicrobial Effectors in the Phagosome Allows SodCII To Contribute to Virulence in Salmonella enterica Serovar Typhimurium." Journal of Bacteriology 192, no. 8 (February 12, 2010): 2140–49. http://dx.doi.org/10.1128/jb.00016-10.
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ABSTRACT Salmonella enterica serovar Typhimurium replicates in macrophages, where it is subjected to antimicrobial substances, including superoxide, antimicrobial peptides, and proteases. The bacterium produces two periplasmic superoxide dismutases, SodCI and SodCII. Although both are expressed during infection, only SodCI contributes to virulence in the mouse by combating phagocytic superoxide. The differential contribution to virulence is at least partially due to inherent differences in the SodCI and SodCII proteins that are independent of enzymatic activity. SodCII is protease sensitive, and like other periplasmic proteins, it is released by osmotic shock. In contrast, SodCI is protease resistant and is retained within the periplasm after osmotic shock, a phenomenon that we term “tethering.” We hypothesize that in the macrophage, antimicrobial peptides transiently disrupt the outer membrane. SodCII is released and/or phagocytic proteases gain access to the periplasm, and SodCII is degraded. SodCI is tethered within the periplasm and is protease resistant, thereby remaining to combat superoxide. Here we test aspects of this model. SodCII was released by the antimicrobial peptide polymyxin B or a mouse macrophage antimicrobial peptide (CRAMP), while SodCI remained tethered within the periplasm. A Salmonella pmrA constitutive mutant no longer released SodCII in vitro. Moreover, in the constitutive pmrA background, SodCII could contribute to survival of Salmonella during infection. SodCII also provided a virulence benefit in mice genetically defective in production of CRAMP. Thus, consistent with our model, protecting the outer membrane against antimicrobial peptides allows SodCII to contribute to virulence in vivo. These data also suggest direct in vivo cooperative interactions between macrophage antimicrobial effectors.
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Mount, Kristy L. B., Carisa A. Townsend, and Margaret E. Bauer. "Haemophilus ducreyi Is Resistant to Human Antimicrobial Peptides." Antimicrobial Agents and Chemotherapy 51, no. 9 (July 9, 2007): 3391–93. http://dx.doi.org/10.1128/aac.00473-07.
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ABSTRACT We examined the susceptibility of Haemophilus ducreyi to antimicrobial peptides likely to be encountered in vivo during human infection. H. ducreyi was significantly more resistant than Escherichia coli to the bactericidal effects of all peptides tested. Class I and II H. ducreyi strains exhibited similar levels of resistance to antimicrobial peptides.
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Arias, Mauricio, Ashley L. Hilchie, Evan F. Haney, Jan G. M. Bolscher, M. Eric Hyndman, Robert E. W. Hancock, and Hans J. Vogel. "Anticancer activities of bovine and human lactoferricin-derived peptides." Biochemistry and Cell Biology 95, no. 1 (February 2017): 91–98. http://dx.doi.org/10.1139/bcb-2016-0175.
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Lactoferrin (LF) is a mammalian host defense glycoprotein with diverse biological activities. Peptides derived from the cationic region of LF possess cytotoxic activity against cancer cells in vitro and in vivo. Bovine lactoferricin (LFcinB), a peptide derived from bovine LF (bLF), exhibits broad-spectrum anticancer activity, while a similar peptide derived from human LF (hLF) is not as active. In this work, several peptides derived from the N-terminal regions of bLF and hLF were studied for their anticancer activities against leukemia and breast-cancer cells, as well as normal peripheral blood mononuclear cells. The cyclized LFcinB-CLICK peptide, which possesses a stable triazole linkage, showed improved anticancer activity, while short peptides hLF11 and bLF10 were not cytotoxic to cancer cells. Interestingly, hLF11 can act as a cell-penetrating peptide; when combined with the antimicrobial core sequence of LFcinB (RRWQWR) through either a Pro or Gly–Gly linker, toxicity to Jurkat cells increased. Together, our work extends the library of LF-derived peptides tested for anticancer activity, and identified new chimeric peptides with high cytotoxicity towards cancerous cells. Additionally, these results support the notion that short cell-penetrating peptides and antimicrobial peptides can be combined to create new adducts with increased potency.
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Mwangi, James, Yizhu Yin, Gan Wang, Min Yang, Ya Li, Zhiye Zhang, and Ren Lai. "The antimicrobial peptide ZY4 combats multidrug-resistantPseudomonas aeruginosaandAcinetobacter baumanniiinfection." Proceedings of the National Academy of Sciences 116, no. 52 (December 16, 2019): 26516–22. http://dx.doi.org/10.1073/pnas.1909585117.
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The emergence of carbapenem-resistantAcinetobacter baumanniiandPseudomonas aeruginosaraises fears of untreatable infections and poses the greatest health threats. Antimicrobial peptides (AMPs) are regarded as the most ideal solution to this menace. In this study, a set of peptides was designed based on our previously reported peptide cathelicidin-BF-15, and the lead peptide ZY4, a cyclic peptide stabilized by a disulfide bridge with high stability in vivo (the half-life is 1.8 h), showed excellent activity againstP. aeruginosaandA. baumannii, including standard and clinical multidrug-resistant (MDR) strains. ZY4 killed bacteria by permeabilizing the bacterial membrane and showed low propensity to induce resistance, exhibited biofilm inhibition and eradication activities, and also killed persister cells. Notably, administration of ZY4 decreased susceptibility to lung infection byP. aeruginosaand suppressed dissemination ofP. aeruginosaandA. baumanniito target organs in a mouse septicemia infection model. These findings identify ZY4 as an ideal candidate against MDR bacterial infections.
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Buonocore, Francesco, Anna Maria Fausto, Giulia Della Pelle, Tomislav Roncevic, Marco Gerdol, and Simona Picchietti. "Attacins: A Promising Class of Insect Antimicrobial Peptides." Antibiotics 10, no. 2 (February 20, 2021): 212. http://dx.doi.org/10.3390/antibiotics10020212.
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Insects produce a large repertoire of antimicrobial peptides (AMPs) as the first line of defense against bacteria, viruses, fungi or parasites. These peptides are produced from a large precursor that contains a signal domain, which is cleaved in vivo to produce the mature protein with antimicrobial activity. At present, AMPs from insects include several families which can be classified as cecropins, ponericins, defensins, lebocins, drosocin, Metchnikowin, gloverins, diptericins and attacins according to their structure and/or function. This short review is focused on attacins, a class of glycine-rich peptides/proteins that have been first discovered in the cecropia moth (Hyalophora cecropia). They are a rather heterogeneous group of immunity-related proteins that exhibit an antimicrobial effect mainly against Gram-negative bacteria. Here, we discuss different attacin and attacin-like AMPs that have been discovered so far and analyze their structure and phylogeny. Special focus is given to the physiological importance and mechanism of action of attacins against microbial pathogens together with their potential pharmacological applications, emphasizing their roles as antimicrobials.
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Dong, Na, Qingquan Ma, Anshan Shan, Yinfeng Lv, Wanning Hu, Yao Gu, and Yuzhi Li. "Strand Length-Dependent Antimicrobial Activity and Membrane-Active Mechanism of Arginine- and Valine-Rich β-Hairpin-Like Antimicrobial Peptides." Antimicrobial Agents and Chemotherapy 56, no. 6 (March 5, 2012): 2994–3003. http://dx.doi.org/10.1128/aac.06327-11.
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ABSTRACTAntimicrobial peptides with amphipathic β-hairpin-like structures have potent antimicrobial properties and low cytotoxicity. The effect of VR or RV motifs on β-hairpin-like antimicrobial peptides has not been investigated. In this study, a series of β-hairpin-like peptides, Ac-C(VR)nDPG (RV)nC-NH2(n= 1, 2, 3, 4, or 5), were synthesized, and the effect of chain length on antimicrobial activity was evaluated. The antimicrobial activity of the peptides initially increased and then decreased with chain length. Longer peptides stimulated the toxicity to mammalian cells. VR3, a 16-mer peptide with seven amino acids in the strand, displayed the highest therapeutic index and represents the optimal chain length. VR3 reduced bacterial counts in the mouse peritoneum and increased the survival rate of mice at 7 days afterSalmonella entericaserovar Typhimurium infectionin vivo. The circular dichroism (CD) spectra demonstrated that the secondary structure of the peptides was a β-hairpin or β-sheet in the presence of an aqueous and membrane-mimicking environment. VR3 had the same degree of penetration into the outer and inner membranes as melittin. Experiments simulating the membrane environment showed that Trp-containing VRW3 (a VR3 analog) tends to interact preferentially with negatively charged vesicles in comparison to zwitterionic vesicles, which supports the biological activity data. Additionally, VR3 resulted in greater membrane damage than melittin as determined using a flow cytometry-based membrane integrity assay. Collectively, the data for synthetic lipid vesicles and whole bacteria demonstrated that the VR3 peptide killed bacteria via targeting the cell membrane. This assay could be an effective pathway to screen novel candidates for antibiotic development.
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Ciociola, Tecla, Thelma A. Pertinhez, Tiziano De Simone, Walter Magliani, Elena Ferrari, Silvana Belletti, Tiziana D’Adda, Stefania Conti, and Laura Giovati. "In Vitro and In Vivo Anti-Candida Activity and Structural Analysis of Killer Peptide (KP)-Derivatives." Journal of Fungi 7, no. 2 (February 10, 2021): 129. http://dx.doi.org/10.3390/jof7020129.
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The previously described decapeptide AKVTMTCSAS (killer peptide, KP), derived from the variable region of a recombinant yeast killer toxin-like anti-idiotypic antibody, proved to exert a variety of antimicrobial, antiviral, and immunomodulatory activities. It also showed a peculiar self-assembly ability, likely responsible for the therapeutic effect in animal models of systemic and mucosal candidiasis. The present study analyzed the biological and structural properties of peptides derived from KP by substitution or deletion of the first residue, leaving unchanged the remaining amino acids. The investigated peptides proved to exert differential in vitro and/or in vivo anti-Candida activity without showing toxic effects on mammalian cells. The change of the first residue in KP amino acidic sequence affected the conformation of the resulting peptides in solution, as assessed by circular dichroism spectroscopy. KP-derivatives, except one, were able to induce apoptosis in yeast cells, like KP itself. ROS production and changes in mitochondrial transmembrane potential were also observed. Confocal and transmission electron microscopy studies allowed to establish that selected peptides could penetrate within C. albicans cells and cause gross morphological alterations. Overall, the physical and chemical properties of the first residue were found to be important for peptide conformation, candidacidal activity and possible mechanism of action. Small antimicrobial peptides could be exploited for the development of a new generation of antifungal drugs, given their relative low cost and ease of production as well as the possibility of devising novel delivery systems.
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Ciociola, Tecla, Walter Magliani, Tiziano De Simone, Thelma A. Pertinhez, Stefania Conti, Giorgio Cozza, Oriano Marin, and Laura Giovati. "In Silico Predicted Antifungal Peptides: In Vitro and In Vivo Anti-Candida Activity." Journal of Fungi 7, no. 6 (May 31, 2021): 439. http://dx.doi.org/10.3390/jof7060439.
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It has been previously demonstrated that synthetic antibody-derived peptides could exert a significant activity in vitro, ex vivo, and/or in vivo against microorganisms and viruses, as well as immunomodulatory effects through the activation of immune cells. Based on the sequence of previously described antibody-derived peptides with recognized antifungal activity, an in silico analysis was conducted to identify novel antifungal candidates. The present study analyzed the candidacidal and structural properties of in silico designed peptides (ISDPs) derived by amino acid substitutions of the parent peptide KKVTMTCSAS. ISDPs proved to be more active in vitro than the parent peptide and all proved to be therapeutic in Galleria mellonella candidal infection, without showing toxic effects on mammalian cells. ISDPs were studied by circular dichroism spectroscopy, demonstrating different structural organization. These results allowed to validate a consensus sequence for the parent peptide KKVTMTCSAS that may be useful in the development of novel antimicrobial molecules.
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Loutet, Slade A., Ronald S. Flannagan, Cora Kooi, Pamela A. Sokol, and Miguel A. Valvano. "A Complete Lipopolysaccharide Inner Core Oligosaccharide Is Required for Resistance of Burkholderia cenocepacia to Antimicrobial Peptides and Bacterial Survival In Vivo." Journal of Bacteriology 188, no. 6 (March 15, 2006): 2073–80. http://dx.doi.org/10.1128/jb.188.6.2073-2080.2006.
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ABSTRACT Burkholderia cenocepacia is an important opportunistic pathogen of patients with cystic fibrosis. This bacterium is inherently resistant to a wide range of antimicrobial agents, including high concentrations of antimicrobial peptides. We hypothesized that the lipopolysaccharide (LPS) of B. cenocepacia is important for both virulence and resistance to antimicrobial peptides. We identified hldA and hldD genes in B. cenocepacia strain K56-2. These two genes encode enzymes involved in the modification of heptose sugars prior to their incorporation into the LPS core oligosaccharide. We constructed a mutant, SAL1, which was defective in expression of both hldA and hldD, and by performing complementation studies we confirmed that the functions encoded by both of these B. cenocepacia genes were needed for synthesis of a complete LPS core oligosaccharide. The LPS produced by SAL1 consisted of a short lipid A-core oligosaccharide and was devoid of O antigen. SAL1 was sensitive to the antimicrobial peptides polymyxin B, melittin, and human neutrophil peptide 1. In contrast, another B. cenocepacia mutant strain that produced complete lipid A-core oligosaccharide but lacked polymeric O antigen was not sensitive to polymyxin B or melittin. As determined by the rat agar bead model of lung infection, the SAL1 mutant had a survival defect in vivo since it could not be recovered from the lungs of infected rats 14 days postinfection. Together, these data show that the B. cenocepacia LPS inner core oligosaccharide is needed for in vitro resistance to three structurally unrelated antimicrobial peptides and for in vivo survival in a rat model of chronic lung infection.
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Gank, Kimberly D., Michael R. Yeaman, Satoshi Kojima, Nannette Y. Yount, Hyunsook Park, John E. Edwards, Scott G. Filler, and Yue Fu. "SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans." Eukaryotic Cell 7, no. 8 (May 30, 2008): 1318–27. http://dx.doi.org/10.1128/ec.00402-07.
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ABSTRACT Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptide-resistant strain of C. albicans, 36082R, is hypervirulent in animal models versus its susceptible counterpart (36082S). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082S and 36082R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082R than in 36082S. In isogenic backgrounds, ssd1Δ/ssd1Δ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1Δ/ssd1Δ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.
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Easton, Donna M., Shuhua Ma, Neeloffer Mookherjee, Pamela Hamill, David Lynn, Jennifer Gardy, Sarah Mullaly, et al. "Immunomodulatory activity of synthetic innate defence regulators (IDRs) (134.45)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 134.45. http://dx.doi.org/10.4049/jimmunol.182.supp.134.45.
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Abstract Cationic host defence (antimicrobial) peptides, e.g. cathelicidin LL-37, have a variety of immunomodulatory activities that favour the safe resolution of infections. We have studied novel synthetic cationic innate defence regulator peptides that are not directly antimicrobial but are anti-infective in vivo, due to modulation of innate immunity. A range of peptides derived from the small bovine peptide bactenecin were screened for immunomodulatory activities in vitro; e.g. promotion of chemokine production and suppression of pro-inflammatory cytokines. Since innate immunity is complex, involving >1,500 gene products, a systems biology approach was utilized to characterize peptide modulation of innate immunity, including analysis of receptors, signalling pathways, transcription factors and downstream genes. To permit visualization and bioinformatic analysis of complex events, an innate immunity database (www.innatedb.ca), a network visualization tool (Cerebral) and downstream analysis tools (e.g. pathway overrepresentation analysis) were developed and provided insight into how this selective modulation occurs. In vivo data indicate that these activities provide protection in animal model infections of Gram positive and Gram negative bacterial infections as well as severe malaria. Thus IDRs have great potential for use as novel anti-infective agents. Supported by Genome BC, FNIH and CIHR.
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Newstead, Logan L., Katarina Varjonen, Tim Nuttall, and Gavin K. Paterson. "Staphylococcal-Produced Bacteriocins and Antimicrobial Peptides: Their Potential as Alternative Treatments for Staphylococcus aureus Infections." Antibiotics 9, no. 2 (January 21, 2020): 40. http://dx.doi.org/10.3390/antibiotics9020040.
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Staphylococcus aureus is an important pathogen of both humans and animals, implicated in a wide range of infections. The emergence of antibiotic resistance has resulted in S. aureus strains that are resistant to almost all available antibiotics, making treatment a clinical challenge. Development of novel antimicrobial approaches is now a priority worldwide. Bacteria produce a range of antimicrobial peptides; the most diverse of these being bacteriocins. Bacteriocins are ribosomally synthesised peptides, displaying potent antimicrobial activity usually against bacteria phylogenetically related to the producer strain. Several bacteriocins have been isolated from commensal coagulase-negative staphylococci, many of which display inhibitory activity against S. aureus in vitro and in vivo. The ability of these bacteriocins to target biofilm formation and their novel mechanisms of action with efficacy against antibiotic-resistant bacteria make them strong candidates as novel therapeutic antimicrobials. The use of genome-mining tools will help to advance identification and classification of bacteriocins. This review discusses the staphylococcal-derived antimicrobial peptides displaying promise as novel treatments for S. aureus infections.
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Sabri, Miloud, Kaoutar El Handi, Franco Valentini, Angelo De Stradis, El Hassan Achbani, Rachid Benkirane, and Toufic Elbeaino. "Exploring Antimicrobial Peptides Efficacy against Fire Blight (Erwinia amylovora)." Plants 12, no. 1 (December 26, 2022): 113. http://dx.doi.org/10.3390/plants12010113.
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Antimicrobial peptides (AMPs) are a various group of molecules found in a wide range of organisms and act as a defense mechanism against different kinds of infectious pathogens (bacteria, viruses, and fungi, etc.). This study explored the antibacterial activity of nine candidates reported in the literature for their effect on human and animal bacteria, (i.e., Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa) against Erwinia amylovora (E. amylovora), the causal agent of fire blight disease on pome fruits. The antibacterial activity of these peptides against E. amylovora was evaluated in vitro using viable-quantitative PCR (v-qPCR), fluorescence microscopy (FM), optical density (OD), and transmission electron microscopy (TEM), while the in vivo control efficacy was evaluated in treating experimental fire blight on pear fruits. With a view to their safe and ecofriendly field use in the future, the study also used animal and plant eukaryotic cells to evaluate the possible toxicity of these AMPs. Results in vitro showed that KL29 was the most potent peptide in inhibiting E. amylovora cell proliferation. In addition, the results of v-qPCR, FM, and TEM showed that KL29 has a bifunctional mechanism of action (lytic and non-lytic) when used at different concentrations against E. amylovora. KL29 reduced fire blight symptoms by 85% when applied experimentally in vivo. Furthermore, it had no impact on animal or plant cells, thus demonstrating its potential for safe use as an antibacterial agent. This study sheds light on a new and potent antibacterial peptide for E. amylovora and its modes of action, which could be exploited to develop sustainable treatments for fire blight.
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Formaggio, Daniela M. D., Jéssica A. Magalhães, Vitor M. Andrade, Katia Conceição, Juliana M. Anastácio, Gabrielli S. Santiago, Denise C. Arruda, and Dayane B. Tada. "Co-Functionalization of Gold Nanoparticles with C7H2 and HuAL1 Peptides: Enhanced Antimicrobial and Antitumoral Activities." Pharmaceutics 14, no. 7 (June 23, 2022): 1324. http://dx.doi.org/10.3390/pharmaceutics14071324.
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The functionalization of nanoparticles with therapeutic peptides has been pointed out as a promising strategy to improve the applications of these molecules in the field of health sciences. Peptides are highly bioactive but face several limitations such as low bioavailability due to the difficulty of overcoming the physiological barriers in the body and their degradation by enzymes. In this work, gold nanoparticles (AuNPs) were co-functionalized with two therapeutic peptides simultaneously. The peptides from the complementary determining region of monoclonal antibodies, composed of the amino acid sequences YISCYNGATSYNQKFK (C7H2) and RASQSVSSYLA (HuAL1) were chosen for having exhibited antitumor and antimicrobial activity before. The peptides-conjugated AuNPs were characterized regarding size, morphology, and metal concentration by using TEM, dynamic light scattering, and ICP-OES techniques. Then, peptides-conjugated AuNPs were evaluated regarding the antimicrobial activity against E. coli, P. aeruginosa, and C. albicans. The antitumoral activity was evaluated in vitro by cell viability assays with metastatic melanoma cell line (B16F10-Nex2) and the cytotoxicity was evaluated against human foreskin fibroblast (Hs68) cell line. Finally, in vivo assays were performed by using a syngeneic animal model of metastatic melanoma. Our findings have highlighted the potential application of the dual-peptide AuNPs in order to enhance the antitumor and antimicrobial activity of peptides.
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Kuppusamy, Willcox, Black, and Kumar. "Short Cationic Peptidomimetic Antimicrobials." Antibiotics 8, no. 2 (April 18, 2019): 44. http://dx.doi.org/10.3390/antibiotics8020044.
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The rapid growth of antimicrobial resistance against several frontline antibiotics has encouraged scientists worldwide to develop new alternatives with unique mechanisms of action. Antimicrobial peptides (AMPs) have attracted considerable interest due to their rapid killing and broad-spectrum activity. Peptidomimetics overcome some of the obstacles of AMPs such as high cost of synthesis, short half-life in vivo due to their susceptibility to proteolytic degradation, and issues with toxicity. This review will examine the development of short cationic peptidomimetics as antimicrobials.
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Liu, He, Na Yang, Da Teng, Ruoyu Mao, Ya Hao, Xuanxuan Ma, and Jianhua Wang. "Design and Pharmacodynamics of Recombinant Fungus Defensin NZL with Improved Activity against Staphylococcus hyicus In Vitro and In Vivo." International Journal of Molecular Sciences 22, no. 11 (May 21, 2021): 5435. http://dx.doi.org/10.3390/ijms22115435.
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Staphylococcus hyicus is recognized as a leading pathogen of exudative epidermitis in modern swine industry. Antimicrobial peptides are attractive candidates for development as potential therapeutics to combat the serious threats of the resistance of S. hyicus. In this study, a series of derivatives were designed based on the NZ2114 template with the aim of obtaining peptides with more potent antimicrobial activity through changing net positive charge or hydrophobicity. Among them, a variant designated as NZL was highly expressed in Pichia pastoris (P. pastoris) with total secreted protein of 1505 mg/L in a 5-L fermenter and exhibited enhanced antimicrobial activity relative to parent peptide NZ2114. Additionally, NZL could kill over 99% of S. hyicus NCTC10350 in vitro within 8 h and in Hacat cells. The results of membrane permeabilization assay, morphological observations, peptide localization assay showed that NZL had potent activity against S. hyicus, which maybe kill S. hyicus through action on the cell wall. NZL also showed an effective therapy in a mouse peritonitis model caused by S. hyicus, superior to NZ2114 or ceftriaxone. Overall, these findings can contribute to explore a novel potential candidate against S. hyicus infections.
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Alavo, Thiery B. C., and Gary B. Dunphy. "Bacterial formyl peptides affect the innate cellular antimicrobial responses of larval Galleria mellonella (Insecta: Lepidoptera)." Canadian Journal of Microbiology 50, no. 4 (April 1, 2004): 279–89. http://dx.doi.org/10.1139/w04-014.
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The non-self cellular (hemocytic) responses of Galleria mellonella larvae, including the attachment to slides and the removal of the bacteria Xenorhabdus nematophila and Bacillus subtilis from the hemolymph, were affected by N-formyl peptides. Both N-formyl methionyl-leucyl-phenylalanine (fMLF) and the ester derivative decreased hemocyte adhesion in vitro, and both elevated hemocyte counts and suppressed the removal of both X. nematophila and B. subtilis from the hemolymph in vivo. The amide derivative and the antagonist tertiary-butoxy-carbonyl-methionyl-leucyl-phenylalanine (tBOC) increased hemocyte attachment to glass. The fMLF suppressed protein discharge from monolayers of granular cells with and without bacterial stimulation, while tBOC stimulated protein discharge. The peptide tBOC offset the effects of fMLF in vitro and in vivo. This is the first report implying the existence of formyl peptide receptors on insect hemocytes in which the compounds fMLF and tBOC inhibited and activated hemocyte activity, respectively.Key words: formyl peptides, hemocytes, Xenorhabdus, Bacillus.
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Silva, Osmar N., Marcelo D. T. Torres, Jicong Cao, Elaine S. F. Alves, Leticia V. Rodrigues, Jarbas M. Resende, Luciano M. Lião, et al. "Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties." Proceedings of the National Academy of Sciences 117, no. 43 (October 12, 2020): 26936–45. http://dx.doi.org/10.1073/pnas.2012379117.
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Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials.
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Ciociola, Tecla, Thelma A. Pertinhez, Laura Giovati, Martina Sperindè, Walter Magliani, Elena Ferrari, Rita Gatti, et al. "Dissecting the Structure-Function Relationship of a Fungicidal Peptide Derived from the Constant Region of Human Immunoglobulins." Antimicrobial Agents and Chemotherapy 60, no. 4 (February 8, 2016): 2435–42. http://dx.doi.org/10.1128/aac.01753-15.
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ABSTRACTSynthetic peptides encompassing sequences related to the complementarity-determining regions of antibodies or derived from their constant region (Fc peptides) were proven to exert differential antimicrobial, antiviral, antitumor, and/or immunomodulatory activitiesin vitroand/orin vivo, regardless of the specificity and isotype of the parental antibody. Alanine substitution derivatives of these peptides exhibited unaltered, increased, or decreased candidacidal activitiesin vitro. The bioactive IgG-derived Fc N10K peptide (NQVSLTCLVK) spontaneously self-assembles, a feature previously recognized as relevant for the therapeutic activity of another antibody-derived peptide. We evaluated the contribution of each residue to the peptide self-assembling capability by circular-dichroism spectroscopy. The interaction of the N10K peptide and its derivatives withCandida albicanscells was studied by confocal, transmission, and scanning electron microscopy. The apoptosis and autophagy induction profiles in yeast cells treated with the peptides were evaluated by flow cytometry, and the therapeutic efficacy against candidal infection was studied in aGalleria mellonellamodel. Overall, the results indicate a critical role for some residues in the self-assembly process and a correlation of that capability with the candidacidal activities of the peptidesin vitroand their therapeutic effectsin vivo.
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Choi, Sungwook, Andre Isaacs, Dylan Clements, Dahui Liu, Hyemin Kim, Richard W. Scott, Jeffrey D. Winkler, and William F. DeGrado. "De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers." Proceedings of the National Academy of Sciences 106, no. 17 (April 9, 2009): 6968–73. http://dx.doi.org/10.1073/pnas.0811818106.
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The emergence of drug-resistant bacteria has compromised the use of many conventional antibiotics, leading to heightened interest in a variety of antimicrobial peptides. Although these peptides have attractive potential as antibiotics, their size, stability, tissue distribution, and toxicity have hampered attempts to harness these capabilities. To address such issues, we have developed small (molecular mass <1,000 Da) arylamide foldamers that mimic antimicrobial peptides. Hydrogen-bonded restraints in the arylamide template rigidify the conformation via hydrogen bond formation and increase activity toward Staphylococcus aureus and Escherichia coli. The designed foldamers are highly active against S. aureus in an animal model. These results demonstrate the application of foldamer templates as therapeutics.
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Bilska, Bernadetta, Urszula Godlewska, Milena Damulewicz, Krzysztof Murzyn, Mateusz Kwitniewski, Joanna Cichy, and Elżbieta Pyza. "Antimicrobial Properties of a Peptide Derived from the Male Fertility Factor kl2 Protein of Drosophila melanogaster." Current Issues in Molecular Biology 44, no. 3 (February 28, 2022): 1169–81. http://dx.doi.org/10.3390/cimb44030076.
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Antimicrobial peptides (AMPs) are important components of innate immunity. Here, we report the antimicrobial properties of a peptide derived from the Male fertility factor kl2 (MFF-kl2) protein of Drosophila melanogaster, which was identified as a functional analog of the mammalian antibacterial chemerin-p4 peptide. The antimicrobial activity of multifunctional chemerin is mainly associated with a domain localized in the middle of the chemerin sequence, Val66-Pro85 peptide (chemerin-p4). Using bioinformatic tools, we found homologs of the chemerin-p4 peptide in the proteome of D. melanogaster. One of them is MFF-p1, which is a part of the MFF kl2 protein, encoded by the gene male fertility factor kl2 (kl-2) located on the long arm of the Y chromosome. The second detected peptide (Z-p1) is a part of the Zizimin protein belonging to DOCK family, which is involved in cellular signaling processes. After testing the antimicrobial properties of both peptides, we found that only MFF-p1 possesses these properties. Here, we demonstrate its antimicrobial potential both in vitro and in vivo after infecting D. melanogaster with bacteria. MFF-p1 strongly inhibits the viable counts of E. coli and B. subtilis after 2 h of treatment and disrupts bacterial cells. The expression of kl-2 is regulated by exposure to bacteria and by the circadian clock.
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Luo, Ying, and Yuzhu Song. "Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities." International Journal of Molecular Sciences 22, no. 21 (October 22, 2021): 11401. http://dx.doi.org/10.3390/ijms222111401.
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Antimicrobial peptides (AMPs) are regarded as a new generation of antibiotics. Besides antimicrobial activity, AMPs also have antibiofilm, immune-regulatory, and other activities. Exploring the mechanism of action of AMPs may help in the modification and development of AMPs. Many studies were conducted on the mechanism of AMPs. The present review mainly summarizes the research status on the antimicrobial, anti-inflammatory, and antibiofilm properties of AMPs. This study not only describes the mechanism of cell wall action and membrane-targeting action but also includes the transmembrane mechanism of intracellular action and intracellular action targets. It also discusses the dual mechanism of action reported by a large number of investigations. Antibiofilm and anti-inflammatory mechanisms were described based on the formation of biofilms and inflammation. This study aims to provide a comprehensive review of the multiple activities and coordination of AMPs in vivo, and to fully understand AMPs to realize their therapeutic prospect.
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Yang, Shu-Jing, Xiang-Hong Xiao, Yi-Gang Xu, Dan-Dan Li, Long-Hui Chai, and Jing-Yu Zhang. "Induction of antimicrobial peptides from Rana dybowskii under Rana grylio virus stress, and bioactivity analysis." Canadian Journal of Microbiology 58, no. 7 (July 2012): 848–55. http://dx.doi.org/10.1139/w2012-055.
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The skin glands of Ranidae are a rich source of antimicrobial peptides. In this study, the genomic RNA of Rana dybowskii was extracted from its skin while under Rana grylio virus stress. Five new cDNA sequences encoding 5 mature peptides, Ranatuerin-2YJ (GLMDIFKVAVNKLLAAGMNKPRCKAAHC), Dybowskin-YJb (IIPLPLGYFAKKP), Dybowskin-YJa (IIPLPLGYFAKKKKKKDPVPLDQ), Temperin-YJa (VLPLLETCSMTCWENNQTFGK), and Temperin-YJb (VLPLVGNLLNDLLGK), were obtained by reverse transcription polymerase chain reaction with a pair of degenerate primers designed according to the conserved terminal sequences of cDNA encoding antimicrobial peptide precursors of genus Rana. The antimicrobial activities of the peptides were analyzed, and the results demonstrated that all these peptides showed a significant anti-Rana grylio virus activity, and the virus was gradually cleared with the increase in gene expression. Among the 5 peptides obtained in this work, Ranatuerin-2YJ also showed a broad-spectrum anti-Gram-positive bacteria and anti-Gram-negative bacteria activity with a minimal inhibitory concentration of 22.5 µg/mL and 7.64% hemolysis activity, both of which were significantly lower (p < 0.05) than that of the other peptides. Moreover, Ranatuerin-2YJ was widely distributed in the skin, liver, spleen, and blood of R. dybowskii, while the other 4 peptides could only be cloned from the skin, indicating that the Ranatuerin-2YJ in vivo plays an important role in the protection against pathogen invasion.
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Arrighi, Romanico B. G., Chikashi Nakamura, Jun Miyake, Hilary Hurd, and J. Grant Burgess. "Design and Activity of Antimicrobial Peptides against Sporogonic-Stage Parasites Causing Murine Malarias." Antimicrobial Agents and Chemotherapy 46, no. 7 (July 2002): 2104–10. http://dx.doi.org/10.1128/aac.46.7.2104-2110.2002.
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ABSTRACT Insects produce several types of peptides to combat a broad spectrum of invasive pathogenic microbes, including protozoans. However, despite this defense response, infections are often established. Our aim was to design novel peptides that produce high rates of mortality among protozoa of the genus Plasmodium, the malaria parasites. Using existing antimicrobial peptide sequences as templates, we designed and synthesized three short novel hybrids, designated Vida1 to Vida3. Each has a slightly different predicted secondary structure. The peptides were tested against sporogonic stages of the rodent malaria parasites Plasmodium berghei (in vitro and in vivo) and P. yoelii nigeriensis (in vitro). The level of activity varied for each peptide and according to the parasite stage targeted. Vida3 (which is predicted to have large numbers of β sheets and coils but no α helices) showed the highest level of activity, killing the early sporogonic stages in culture and causing highly significant reductions in the prevalence and intensity of infection of P. berghei after oral administration or injection in Anopheles gambiae mosquitoes. The secondary structures of these peptides may play a crucial role in their ability to interact with and kill sporogonic forms of the malaria parasite.
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Jabeen, Mahe, Payel Biswas, Md Touhidul Islam, and Rajesh Paul. "Antiviral Peptides in Antimicrobial Surface Coatings—From Current Techniques to Potential Applications." Viruses 15, no. 3 (February 27, 2023): 640. http://dx.doi.org/10.3390/v15030640.
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The transmission of pathogens through contact with contaminated surfaces is an important route for the spread of infections. The recent outbreak of COVID-19 highlights the necessity to attenuate surface-mediated transmission. Currently, the disinfection and sanitization of surfaces are commonly performed in this regard. However, there are some disadvantages associated with these practices, including the development of antibiotic resistance, viral mutation, etc.; hence, a better strategy is necessary. In recent years, peptides have been studied to be utilized as a potential alternative. They are part of the host immune defense and have many potential in vivo applications in drug delivery, diagnostics, immunomodulation, etc. Additionally, the ability of peptides to interact with different molecules and membrane surfaces of microorganisms has made it possible to exploit them in ex vivo applications such as antimicrobial (antibacterial and antiviral) coatings. Although antibacterial peptide coatings have been studied extensively and proven to be effective, antiviral coatings are a more recent development. Therefore, this study aims to highlight antiviral coating strategies and the current practices and application of antiviral coating materials in personal protective equipment, healthcare devices, and textiles and surfaces in public settings. Here, we have presented a review on potential techniques to incorporate peptides in current surface coating strategies that will serve as a guide for developing cost-effective, sustainable and coherent antiviral surface coatings. We further our discussion to highlight some challenges of using peptides as a surface coating material and to examine future perspectives.
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Ahmed, Aslaa, Gavriella Siman-Tov, Grant Hall, Nishank Bhalla, and Aarthi Narayanan. "Human Antimicrobial Peptides as Therapeutics for Viral Infections." Viruses 11, no. 8 (August 1, 2019): 704. http://dx.doi.org/10.3390/v11080704.
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Successful in vivo infection following pathogen entry requires the evasion and subversion of multiple immunological barriers. Antimicrobial peptides (AMPs) are one of the first immune pathways upregulated during infection by multiple pathogens, in multiple organs in vivo. In humans, there are many classes of AMPs exhibiting broad antimicrobial activities, with defensins and the human cathelicidin LL-37 being the best studied examples. Whereas historically the efficacy and therapeutic potential of AMPs against bacterial infection has been the primary focus of research, recent studies have begun to elucidate the antiviral properties of AMPs as well as their role in regulation of inflammation and chemoattraction. AMPs as therapeutic tools seem especially promising against emerging infectious viral pathogens for which no approved vaccines or treatments are currently available, such as dengue virus (DENV) and Zika virus (ZIKV). In this review, we summarize recent studies elucidating the efficacy and diverse mechanisms of action of various classes of AMPs against multiple viral pathogens, as well as the potential use of human AMPs in novel antiviral therapeutic strategies.
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Dartois, Véronique, Jorge Sanchez-Quesada, Edelmira Cabezas, Ellen Chi, Chad Dubbelde, Carrie Dunn, Juan Granja, et al. "Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides." Antimicrobial Agents and Chemotherapy 49, no. 8 (August 2005): 3302–10. http://dx.doi.org/10.1128/aac.49.8.3302-3310.2005.
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ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.
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Casciaro, Bruno, Floriana Cappiello, Maria Rosa Loffredo, Francesca Ghirga, and Maria Luisa Mangoni. "The Potential of Frog Skin Peptides for Anti-Infective Therapies: The Case of Esculentin-1a(1-21)NH2." Current Medicinal Chemistry 27, no. 9 (March 27, 2020): 1405–19. http://dx.doi.org/10.2174/0929867326666190722095408.
Full textAbstract:
Antimicrobial Peptides (AMPs) are the key effectors of the innate immunity and represent promising molecules for the development of new antibacterial drugs. However, to achieve this goal, some problems need to be overcome: (i) the cytotoxic effects at high concentrations; (ii) the poor biostability and (iii) the difficulty in reaching the target site. Frog skin is one of the richest natural storehouses of AMPs, and over the years, many peptides have been isolated from it, characterized and classified into several families encompassing temporins, brevinins, nigrocins and esculentins. In this review, we summarized how the isolation/characterization of peptides belonging to the esculentin-1 family drove us to the design of an analogue, i.e. esculentin-1a(1-21)NH2, with a powerful antimicrobial action and immunomodulatory properties. The peptide had a wide spectrum of activity, especially against the opportunistic Gram-negative bacterium Pseudomonas aeruginosa. We described the structural features and the in vitro/in vivo biological characterization of this peptide as well as the strategies used to improve its biological properties. Among them: (i) the design of a diastereomer carrying Damino acids in order to reduce the peptide’s cytotoxicity and improve its half-life; (ii) the covalent conjugation of the peptide to gold nanoparticles or its encapsulation into poly(lactide- co-glycolide) nanoparticles; and (iii) the peptide immobilization to biomedical devices (such as silicon hydrogel contact lenses) to obtain an antibacterial surface able to reduce microbial growth and attachment. Summing up the best results obtained so far, this review traces all the steps that led these frog-skin AMPs to the direction of peptide-based drugs for clinical use.
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Steinstraesser, Lars, Brian F. Tack, Alan J. Waring, Teresa Hong, Lee M. Boo, Ming-Hui Fan, Daniel I. Remick, Grace L. Su, Robert I. Lehrer, and Stewart C. Wang. "Activity of Novispirin G10 against Pseudomonas aeruginosa In Vitro and in Infected Burns." Antimicrobial Agents and Chemotherapy 46, no. 6 (June 2002): 1837–44. http://dx.doi.org/10.1128/aac.46.6.1837-1844.2002.
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ABSTRACT The emergence of multidrug-resistant microbes has serious implications for managing infection and sepsis and has stimulated efforts to develop alternative treatments, such as antimicrobial peptides. The objective of this study was to test a designer peptide, novispirin G10, against multidrug-resistant microorganisms. By two-stage radial diffusion assays, its activity against such organisms compared favorably with that of standard antibiotics and other antimicrobial peptides. It killed bacteria very rapidly, was nonhemolytic, and was relatively noncytotoxic. The peptide induced an immediate, massive efflux of potassium from Pseudomonas aeruginosa, suggesting that it altered the permeability of its inner membrane. The presence of human serum reduced but did not eliminate its activity. We tested the in vivo activity of novispirin G10 in rats with an infected, partial-thickness burn that covered 20% of their total body surface area. The burned area was seeded with 106 CFU of a Silvadene-resistant P. aeruginosa strain, and 24 h later a single treatment with 0, 1, 3, or 6 mg of synthetic novispirin G10 (n = 16 at each concentration) per kg was given intradermally. Significant bacterial killing (P < 0.0001) was evident within 4 h in each peptide group compared to controls receiving vehicle. Antimicrobial peptides such as novispirin G10 may provide a useful alternative or adjunct to standard antibiotic agents in treating burns or other wound infections.
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Winfred, Sofi Beaula, Gowri Meiyazagan, Jiban J. Panda, Venkateshbabu Nagendrababu, Kandaswamy Deivanayagam, Virander S. Chauhan, and Ganesh Venkatraman. "Antimicrobial activity of cationic peptides in endodontic procedures." European Journal of Dentistry 08, no. 02 (April 2014): 254–60. http://dx.doi.org/10.4103/1305-7456.130626.
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ABSTRACT Objectives: The present study aimed to investigate the antimicrobial and biofilm inhibition activity of synthetic antimicrobial peptides (AMPs) against microbes such as Enterococcus faecalis, Staphylococcus aureus, and Candida albicans which are involved in endodontic infections. Materials and Methods: Agar diffusion test was done to determine the activity of peptides. The morphological changes in E. faecalis and reduction in biofilm formation after treatment with peptides were observed using scanning electron microscope. The efficacy of peptides using an ex vivo dentinal model was determined by polymerase chain reaction and confocal laser scanning microscopy. Platelet aggregation was done to determine the biocompatibility of peptides. Results: Among 11 peptides, two of the amphipathic cationic peptides were found to be highly active against E. faecalis, S. aureus, C. albicans. Efficacy results using dentinal tubule model showed significant reduction in microbial load at 400 μm depth. The peptides were also biocompatible. Conclusion: These results suggest that synthetic AMPs have the potential to be developed as antibacterial agents against microorganisms involved in dental infections and thus could prevent the spread and persistence of endodontic infections improving treatment outcomes and teeth preservation.
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Majchrzykiewicz, Joanna A., Jacek Lubelski, Gert N. Moll, Anneke Kuipers, Jetta J. E. Bijlsma, Oscar P. Kuipers, and Rick Rink. "Production of a Class II Two-Component Lantibiotic of Streptococcus pneumoniae Using the Class I Nisin Synthetic Machinery and Leader Sequence." Antimicrobial Agents and Chemotherapy 54, no. 4 (January 25, 2010): 1498–505. http://dx.doi.org/10.1128/aac.00883-09.
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ABSTRACT Recent studies showed that the nisin modification machinery can successfully dehydrate serines and threonines and introduce lanthionine rings in small peptides that are fused to the nisin leader sequence. This opens up exciting possibilities to produce and engineer larger antimicrobial peptides in vivo. Here we demonstrate the exploitation of the class I nisin production machinery to generate, modify, and secrete biologically active, previously not-yet-isolated and -characterized class II two-component lantibiotics that have no sequence homology to nisin. The nisin synthesis machinery, composed of the modification enzymes NisB and NisC and the transporter NisT, was used to modify and secrete a putative two-component lantibiotic of Streptococcus pneumoniae. This was achieved by genetically fusing the propeptide-encoding sequences of the spr1765 (pneA1) and spr1766 (pneA2) genes to the nisin leader-encoding sequence. The chimeric prepeptides were secreted out of Lactococcus lactis, purified by cation exchange fast protein liquid chromatography, and further characterized. Mass spectrometry analyses demonstrated the presence and partial localization of multiple dehydrated serines and/or threonines and (methyl)lanthionines in both peptides. Moreover, after cleavage of the leader peptide from the prepeptides, both modified propeptides displayed antimicrobial activity against Micrococcus flavus. These results demonstrate that the nisin synthetase machinery can be successfully used to modify and produce otherwise difficult to obtain antimicrobially active lantibiotics.
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Deslouches, Berthony, Kazi Islam, Jodi K. Craigo, Shruti M. Paranjape, Ronald C. Montelaro, and Timothy A. Mietzner. "Activity of the De Novo Engineered Antimicrobial Peptide WLBU2 against Pseudomonas aeruginosa in Human Serum and Whole Blood: Implications for Systemic Applications." Antimicrobial Agents and Chemotherapy 49, no. 8 (August 2005): 3208–16. http://dx.doi.org/10.1128/aac.49.8.3208-3216.2005.
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ABSTRACT Cationic amphipathic peptides have been extensively investigated as a potential source of new antimicrobials that can complement current antibiotic regimens in the face of emerging drug-resistant bacteria. However, the suppression of antimicrobial activity under certain biologically relevant conditions (e.g., serum and physiological salt concentrations) has hampered efforts to develop safe and effective antimicrobial peptides for clinical use. We have analyzed the activity and selectivity of the human peptide LL37 and the de novo engineered antimicrobial peptide WLBU2 in several biologically relevant conditions. The host-derived synthetic peptide LL37 displayed high activity against Pseudomonas aeruginosa but demonstrated staphylococcus-specific sensitivity to NaCl concentrations varying from 50 to 300 mM. Moreover, LL37 potency was variably suppressed in the presence of 1 to 6 mM Mg2+ and Ca2+ ions. In contrast, WLBU2 maintained its activity in NaCl and physiologic serum concentrations of Mg2+ and Ca2+. WLBU2 is able to kill P. aeruginosa (106 CFU/ml) in human serum, with a minimum bactericidal concentration of <9 μM. Conversely, LL37 is inactive in the presence of human serum. Bacterial killing kinetic assays in serum revealed that WLBU2 achieved complete bacterial killing in 20 min. Consistent with these results was the ability of WLBU2 (15 to 20 μM) to eradicate bacteria from ex vivo samples of whole blood. The selectivity of WLBU2 was further demonstrated by its ability to specifically eliminate P. aeruginosa in coculture with human monocytes or skin fibroblasts without detectable adverse effects to the host cells. Finally, WLBU2 displayed potent efficacy against P. aeruginosa in an intraperitoneal infection model using female Swiss Webster mice. These results establish a potential application of WLBU2 in the treatment of bacterial sepsis.