Journal articles on the topic 'Fungal Efflux Pumps'
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1
Cannon, Richard D., Erwin Lamping, Ann R. Holmes, Kyoko Niimi, Philippe V. Baret, Mikhail V. Keniya, Koichi Tanabe, Masakazu Niimi, Andre Goffeau, and Brian C. Monk. "Efflux-Mediated Antifungal Drug Resistance." Clinical Microbiology Reviews 22, no. 2 (April 2009): 291–321. http://dx.doi.org/10.1128/cmr.00051-08.
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SUMMARY Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.
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Holmes, Ann R., Mikhail V. Keniya, Irena Ivnitski-Steele, Brian C. Monk, Erwin Lamping, Larry A. Sklar, and Richard D. Cannon. "The Monoamine Oxidase A Inhibitor Clorgyline Is a Broad-Spectrum Inhibitor of Fungal ABC and MFS Transporter Efflux Pump Activities Which Reverses the Azole Resistance of Candida albicans and Candida glabrata Clinical Isolates." Antimicrobial Agents and Chemotherapy 56, no. 3 (December 27, 2011): 1508–15. http://dx.doi.org/10.1128/aac.05706-11.
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ABSTRACTResistance to the commonly used azole antifungal fluconazole (FLC) can develop due to overexpression of ATP-binding cassette (ABC) and major facilitator superfamily (MFS) plasma membrane transporters. An approach to overcoming this resistance is to identify inhibitors of these efflux pumps. We have developed a pump assay suitable for high-throughput screening (HTS) that uses recombinantSaccharomyces cerevisiaestrains hyperexpressing individual transporters from the opportunistic fungal pathogenCandida albicans. The recombinant strains possess greater resistance to azoles and other pump substrates than the parental host strain. A flow cytometry-based HTS, which measured increased intracellular retention of the fluorescent pump substrate rhodamine 6G (R6G) within yeast cells, was used to screen the Prestwick Chemical Library (PCL) of 1,200 marketed drugs. Nine compounds were identified as hits, and the monoamine oxidase A inhibitor (MAOI) clorgyline was identified as an inhibitor of twoC. albicansABC efflux pumps, CaCdr1p and CaCdr2p. Secondaryin vitroassays confirmed inhibition of pump-mediated efflux by clorgyline. Clorgyline also reversed the FLC resistance ofS. cerevisiaestrains expressing other individual fungal ABC transporters (Candida glabrataCdr1p orCandida kruseiAbc1p) or theC. albicansMFS transporter Mdr1p. Recombinant strains were also chemosensitized by clorgyline to other azoles (itraconazole and miconazole). Importantly, clorgyline showed synergy with FLC against FLC-resistantC. albicansclinical isolates and aC. glabratastrain and inhibited R6G efflux from a FLC-resistantC. albicansclinical isolate. Clorgyline is a novel broad-spectrum inhibitor of two classes of fungal efflux pumps that acts synergistically with azoles against azole-resistantC. albicansandC. glabratastrains.
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de Moraes, Daniel Clemente, Ana Claudia Tessis, Rodrigo Rollin-Pinheiro, Jefferson Luiz Princival, José Augusto Ferreira Perez Villar, Leandro Augusto Barbosa, Eliana Barreto-Bergter, and Antônio Ferreira-Pereira. "Digoxin Derivatives Sensitize a Saccharomyces cerevisiae Mutant Strain to Fluconazole by Inhibiting Pdr5p." Journal of Fungi 8, no. 8 (July 25, 2022): 769. http://dx.doi.org/10.3390/jof8080769.
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The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. Saccharomyces cerevisiae possesses an efflux pump (Pdr5p) homologue to those found in pathogenic yeast. Digoxin is a natural product that inhibits Na+, K+-ATPase. The aim of this study was to evaluate whether digoxin and its derivatives (i.e., DGB, digoxin benzylidene) can inhibit Pdr5p, reversing the resistance to fluconazole in yeasts. An S. cerevisiae mutant strain that overexpresses Pdr5p was used in the assays. The effects of the compounds on yeast growth, efflux activity, and Pdr5p ATPase activity were measured. All derivatives enhanced the antifungal activity of fluconazole against S. cerevisiae, in comparison to fluconazole alone, with FICI values ranging from 0.031 to 0.500. DGB 1 and DGB 3 presented combined effects with fluconazole against a Candida albicans strain, with fractional inhibitory concentration index (FICI) values of 0.625 and 0.281, respectively The compounds also inhibited the efflux of rhodamine 6G and Pdr5p ATPase activity, with IC50 values ranging from 0.41 μM to 3.72 μM. The results suggest that digoxin derivatives impair Pdr5p activity. Considering the homology between Pdr5p and efflux pumps from pathogenic fungi, these compounds are potential candidates to be used in association with fluconazole to treat resistant fungal infections.
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Lopes, Marcos E. R., Tamires A. Bitencourt, Pablo R. Sanches, Maíra P. Martins, Vanderci M. Oliveira, Antonio Rossi, and Nilce M. Martinez-Rossi. "Alternative Splicing in Trichophyton rubrum Occurs in Efflux Pump Transcripts in Response to Antifungal Drugs." Journal of Fungi 8, no. 8 (August 20, 2022): 878. http://dx.doi.org/10.3390/jof8080878.
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Dermatophytes are challenging to treat because they have developed many strategies to neutralize the stress triggered by antifungals. Drug tolerance is achieved by mechanisms such as drug efflux and biofilm formation, and cellular efflux is a consequence of the synergistic and compensatory regulation of efflux pumps. Alternative splicing (AS) has also been considered as a mechanism that enhances fungal adaptive responses. We used RNA-seq data from the dermatophyte Trichophyton rubrum exposed to undecanoic acid (UDA) to search for and validate AS in genes encoding efflux pumps. The magnitude of this phenomenon was evaluated using UDA and other antifungals (caspofungin, itraconazole, and terbinafine) in planktonic and biofilm cultures. In addition to the conventional isoforms, the efflux pump encoded by TERG_04309 presented two intron-retained isoforms. Biofilms trigger the simultaneous production of at least two isoforms. The intron-retained isoforms showed short lengths and topologically different organization. Furthermore, we identified the putative interaction of efflux pumps (TERG_04309 and TERG_04224). Co-expression of these genes suggests a synergistic action in antifungal resistance. Our data provide new insights into drug tolerance related to differential isoform usage and the co-expression of stress-responsive genes, which may lead to higher antifungal resistance, mainly in biofilms.
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Song, Jinxing, Jingwen Zhou, Lei Zhang, and Rongpeng Li. "Mitochondria-Mediated Azole Drug Resistance and Fungal Pathogenicity: Opportunities for Therapeutic Development." Microorganisms 8, no. 10 (October 13, 2020): 1574. http://dx.doi.org/10.3390/microorganisms8101574.
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In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.
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Yamawaki, Chika, Yoshihiro Yamaguchi, Akira Ogita, Toshio Tanaka, and Ken-ichi Fujita. "Dehydrozingerone Exhibits Synergistic Antifungal Activities in Combination with Dodecanol against Budding Yeast via the Restriction of Multidrug Resistance." Planta Medica International Open 5, no. 02 (April 2018): e61-e67. http://dx.doi.org/10.1055/a-0757-7991.
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AbstractDrug resistance in fungal infections has been a more frequent occurrence with the increasing number of immunocompromised patients. In efforts to overcome the problem of fungal drug resistance, we focused on the phenolic compound dehydrozingerone, which is isolated from Zingiber officinale. The effectiveness of this compound on the model yeast Saccharomyces cerevisiae has not been reported. In our study, dehydrozingerone showed a weak antifungal activity against the yeast, but demonstrated a synergistic effect in combination with dodecanol, which typically only restricts cell growth transiently. Efflux of rhodamine 6G through the multidrug efflux pumps was significantly restricted by dehydrozingerone. The transcription level of PDR5, encoding a primary multidrug efflux pump in S. cerevisiae, was enhanced with dodecanol treatment, whereas the level was reduced by dehydrozingerone. These results suggest that dehydrozingerone may be effective for potentiating antifungal activity of other drugs that are expelled from fungi by multidrug transporters like Pdr5p.
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Silva, Laura Nunes, Lívia de Souza Ramos, Simone Santiago Carvalho Oliveira, Lucas Barros Magalhães, Eamim Daidrê Squizani, Lívia Kmetzsch, Marilene Henning Vainstein, Marta Helena Branquinha, and André Luis Souza dos Santos. "Insights into the Multi-Azole Resistance Profile in Candida haemulonii Species Complex." Journal of Fungi 6, no. 4 (October 11, 2020): 215. http://dx.doi.org/10.3390/jof6040215.
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The Candida haemulonii complex (C. duobushaemulonii, C. haemulonii, and C. haemulonii var. vulnera) is composed of emerging, opportunistic human fungal pathogens able to cause invasive infections with high rates of clinical treatment failure. This fungal complex typically demonstrates resistance to first-line antifungals, including fluconazole. In the present work, we have investigated the azole resistance mechanisms expressed in Brazilian clinical isolates forming the C. haemulonii complex. Initially, 12 isolates were subjected to an antifungal susceptibility test, and azole cross-resistance was detected in almost all isolates (91.7%). In order to understand the azole resistance mechanistic basis, the efflux pump activity was assessed by rhodamine-6G. The C. haemulonii complex exhibited a significantly higher rhodamine-6G efflux than the other non-albicans Candida species tested (C. tropicalis, C. krusei, and C. lusitaneae). Notably, the efflux pump inhibitors (Phe-Arg and FK506) reversed the fluconazole and voricolazole resistance phenotypes in the C. haemulonii species complex. Expression analysis indicated that the efflux pump (ChCDR1, ChCDR2, and ChMDR1) and ERG11 genes were not modulated by either fluconazole or voriconazole treatments. Further, ERG11 gene sequencing revealed several mutations, some of which culminated in amino acid polymorphisms, as previously reported in azole-resistant Candida spp. Collectively, these data point out the relevance of drug efflux pumps in mediating azole resistance in the C. haemulonii complex, and mutations in ERG11p may contribute to this resistance profile.
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Ivanov, Marija, Abhilash Kannan, Dejan S. Stojković, Jasmina Glamočlija, Ricardo C. Calhelha, Isabel C. F. R. Ferreira, Dominique Sanglard, and Marina Soković. "Camphor and Eucalyptol—Anticandidal Spectrum, Antivirulence Effect, Efflux Pumps Interference and Cytotoxicity." International Journal of Molecular Sciences 22, no. 2 (January 6, 2021): 483. http://dx.doi.org/10.3390/ijms22020483.
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Candidaalbicans represents one of the most common fungal pathogens. Due to its increasing incidence and the poor efficacy of available antifungals, finding novel antifungal molecules is of great importance. Camphor and eucalyptol are bioactive terpenoid plant constituents and their antifungal properties have been explored previously. In this study, we examined their ability to inhibit the growth of different Candida species in suspension and biofilm, to block hyphal transition along with their impact on genes encoding for efflux pumps (CDR1 and CDR2), ergosterol biosynthesis (ERG11), and cytotoxicity to primary liver cells. Camphor showed excellent antifungal activity with a minimal inhibitory concentration of 0.125–0.35 mg/mL while eucalyptol was active in the range of 2–23 mg/mL. The results showed camphor’s potential to reduce fungal virulence traits, that is, biofilm establishment and hyphae formation. On the other hand, camphor and eucalyptol treatments upregulated CDR1;CDR2 was positively regulated after eucalyptol application while camphor downregulated it. Neither had an impact on ERG11 expression. The beneficial antifungal activities of camphor were achieved with an amount that was non-toxic to porcine liver cells, making it a promising antifungal compound for future development. The antifungal concentration of eucalyptol caused cytotoxic effects and increased expression of efflux pump genes, which suggests that it is an unsuitable antifungal candidate.
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Durães, Fernando, Nikoletta Szemerédi, Decha Kumla, Madalena Pinto, Anake Kijjoa, Gabriella Spengler, and Emília Sousa. "Metabolites from Marine-Derived Fungi as Potential Antimicrobial Adjuvants." Marine Drugs 19, no. 9 (August 25, 2021): 475. http://dx.doi.org/10.3390/md19090475.
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Marine-derived fungi constitute an interesting source of bioactive compounds, several of which exhibit antibacterial activity. These acquire special importance, considering that antimicrobial resistance is becoming more widespread. The overexpression of efflux pumps, capable of expelling antimicrobials out of bacterial cells, is one of the most worrisome mechanisms. There has been an ongoing effort to find not only new antimicrobials, but also compounds that can block resistance mechanisms which can be used in combination with approved antimicrobial drugs. In this work, a library of nineteen marine natural products, isolated from marine-derived fungi of the genera Neosartorya and Aspergillus, was evaluated for their potential as bacterial efflux pump inhibitors as well as the antimicrobial-related mechanisms, such as inhibition of biofilm formation and quorum-sensing. Docking studies were performed to predict their efflux pump action. These compounds were also tested for their cytotoxicity in mouse fibroblast cell line NIH/3T3. The results obtained suggest that the marine-derived fungal metabolites are a promising source of compounds with potential to revert antimicrobial resistance and serve as an inspiration for the synthesis of new antimicrobial drugs.
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Usai, Donatella, Matthew Donadu, Alessandra Bua, Paola Molicotti, Stefania Zanetti, Sandra Piras, Paola Corona, Roberta Ibba, and Antonio Carta. "Enhancement of antimicrobial activity of pump inhibitors associating drugs." Journal of Infection in Developing Countries 13, no. 02 (February 28, 2019): 162–64. http://dx.doi.org/10.3855/jidc.11102.
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Introduction: with the continuous emergence of pathogenic resistance to conventional drugs through efflux pumps, increasing efforts are directed toward discovering efflux inhibitory molecules.
Methodology: in this study three P-glycoprotein (P13CP, P22CP, P34CP) efflux-inhibitors (EIs), belonging to the series of phenoxymethylquinoxalines capable to restore/potentiate the antiproliferative activity of doxorubicin and vincristine against human tumor cell lines and different antibiotics against clinical isolates, were investigated on 10 clinical strains of Candida and 12 clinical and ATCC strains of Gram positive and Gram-negative bacteria.
Results: MFC values of FLC were reduced in all Candida strains by the P22CP and P34CP inhibitors, and in 5/10 fungal strains by the P13CP inhibitor.
Conclusion: novel antibiotics with new modes of action are urgently required to suppress the rise of MDR bacteria. An alternative approach would be to identify molecules that can interfere with the process of efflux.
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Mukherjee, Pranab K., Jyotsna Chandra, Duncan M. Kuhn, and Mahmoud A. Ghannoum. "Mechanism of Fluconazole Resistance in Candida albicans Biofilms: Phase-Specific Role of Efflux Pumps and Membrane Sterols." Infection and Immunity 71, no. 8 (August 2003): 4333–40. http://dx.doi.org/10.1128/iai.71.8.4333-4340.2003.
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ABSTRACT Candida albicans biofilms are formed through three distinct developmental phases and are associated with high fluconazole (FLU) resistance. In the present study, we used a set of isogenic Candida strains lacking one or more of the drug efflux pumps Cdr1p, Cdr2p, and Mdr1p to determine their role in FLU resistance of biofilms. Additionally, variation in sterol profile as a possible mechanism of drug resistance was investigated. Our results indicate that parent and mutant strains formed similar biofilms. However, biofilms formed by double and triple mutants were more susceptible to FLU at 6 h (MIC = 64 and 16 μg/ml, respectively) than the wild-type strain (MIC > 256 μg/ml). At later time points (12 and 48 h), all the strains became resistant to this azole (MIC ≥ 256 μg/ml), indicating lack of involvement of efflux pumps in resistance at late stages of biofilm formation. Northern blot analyses revealed that Candida biofilms expressed CDR and MDR1 genes in all the developmental phases, while planktonic cells expressed these genes only at the 12- and 48-h time points. Functionality of efflux pumps was assayed by rhodamine (Rh123) efflux assays, which revealed significant differences in Rh123 retention between biofilm and planktonic cells at the early phase (P = 0.0006) but not at later stages (12 and 48 h). Sterol analyses showed that ergosterol levels were significantly decreased (P < 0.001) at intermediate and mature phases, compared to those in early-phase biofilms. These studies suggest that multicomponent, phase-specific mechanisms are operative in antifungal resistance of fungal biofilms.
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Swidergall, Marc, and Joachim F. Ernst. "Interplay between Candida albicans and the Antimicrobial Peptide Armory." Eukaryotic Cell 13, no. 8 (June 20, 2014): 950–57. http://dx.doi.org/10.1128/ec.00093-14.
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ABSTRACTAntimicrobial peptides (AMPs) are key elements of innate immunity, which can directly kill multiple bacterial, viral, and fungal pathogens. The medically important fungusCandida albicanscolonizes different host niches as part of the normal human microbiota. Proliferation ofC. albicansis regulated through a complex balance of host immune defense mechanisms and fungal responses. Expression of AMPs against pathogenic fungi is differentially regulated and initiated by interactions of a variety of fungal pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on human cells. Inflammatory signaling and other environmental stimuli are also essential to control fungal proliferation and to prevent parasitism. To persist in the host,C. albicanshas developed a three-phase AMP evasion strategy, including secretion of peptide effectors, AMP efflux pumps, and regulation of signaling pathways. These mechanisms preventC. albicansfrom the antifungal activity of the major AMP classes, including cathelicidins, histatins, and defensins leading to a basal resistance. This minireview summarizes human AMP attack andC. albicansresistance mechanisms and current developments in the use of AMPs as antifungal agents.
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Gabriel, Iwona. "‘Acridines’ as New Horizons in Antifungal Treatment." Molecules 25, no. 7 (March 25, 2020): 1480. http://dx.doi.org/10.3390/molecules25071480.
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Frequent fungal infections in immunocompromised patients and mortality due to invasive mycosis are important clinical problems. Opportunistic pathogenic Candida species remain one of the leading causes of systemic mycosis worldwide. The repertoire of antifungal chemotherapeutic agents is very limited. Although new antifungal drugs such as lanosterol 14α-demethylase and β-glucan synthase inhibitors have been introduced into clinical practice, the development of multidrug resistance has become increasingly significant. The urgency to expand the range of therapeutic options for the treatment of fungal infections has led researchers in recent decades to seek alternative antifungal targets to the conventional ones currently used. Among them, many compounds containing an acridine scaffold have been synthesized and tested. In this review, the applicability of acridines and their functional analogues acridones as antifungal agents is described. Acridine derivatives usage in photoantifungal chemotherapy, interactions with fungal transporters resulting in modulation of efflux/influx pumps and the effect of acridine derivatives on fungal topoisomerases are discussed. This article explores new perspectives on the mechanisms of antifungal acridine-peptide conjugates and acridine-based hybrid molecules to effectively combat fungal infections.
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Czarnecka, Monika, Xymena Połomska, Cristina Restuccia, and Barbara Żarowska. "The Role of Plasma Membrane Pleiotropic Drug Resistance Transporters in the Killer Activity of Debaryomyces hansenii and Wickerhamomyces anomalus Toxins." Toxins 14, no. 3 (February 28, 2022): 180. http://dx.doi.org/10.3390/toxins14030180.
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The killer strains of Debaryomyces hansenii and Wickerhamomyces anomalus species secrete antimicrobial proteins called killer toxins which are active against selected fungal phytopathogens. In our research, we attempted to investigate the role of plasma membrane pleiotropic drug resistance (PDR) transporters (Pdr5p and Snq2p) in the mechanism of defense against killer toxins. Saccharomyces cerevisiae mutant strains with strengthened or weakened pleiotropic drug resistance due to increased or reduced number of mentioned PDR efflux pumps were tested for killer toxin susceptibility. The present study demonstrates the influence of the Snq2p efflux pump in immunity to W.anomalus BS91 killer toxin. It was also shown that the activity of killer toxins of D. hansenii AII4b, KI2a, MI1a and CBS767 strains is regulated by other transporters than those influencing W. anomalus killer toxin activity. In turn, this might be related to the functioning of the Pdr5p transporter and a complex cross-talk between several regulatory multidrug resistance networks. To the best of our knowledge, this is the first study that reports the involvement of PDR transporters in the cell membrane of susceptible microorganisms in resistance to killer yeasts’ toxins.
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Galocha, Mónica, Inês Vieira Costa, and Miguel Cacho Teixeira. "Carrier-Mediated Drug Uptake in Fungal Pathogens." Genes 11, no. 11 (November 9, 2020): 1324. http://dx.doi.org/10.3390/genes11111324.
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Candida, Aspergillus, and Cryptococcus species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by the ability of fungal cells to develop drug resistance mechanisms. Drug effectiveness and drug resistance in human pathogens is very often affected by their “transportome”. Many studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ATP-Binding Cassette and Major Facilitator Superfamily. However, the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi. This review focuses on discussing current knowledge on drug uptake systems in fungal pathogens, highlighting the need for further studies on this topic of great importance. The following subjects are covered: (i) drugs imported by known transporter(s) in pathogenic fungi; and (ii) drugs imported by known transporter(s) in the model yeast Saccharomyces cerevisiae or in human parasites, aimed at the identification of their homologs in pathogenic fungi. Besides its contribution to increase the understanding of drug-pathogen interactions, the practical implications of identifying drug importers in human pathogens are discussed, particularly focusing on drug development strategies.
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Niimi, K., D. R. K. Harding, R. Parshot, A. King, D. J. Lun, A. Decottignies, M. Niimi, et al. "Chemosensitization of Fluconazole Resistance in Saccharomyces cerevisiae and Pathogenic Fungi by a d-Octapeptide Derivative." Antimicrobial Agents and Chemotherapy 48, no. 4 (April 2004): 1256–71. http://dx.doi.org/10.1128/aac.48.4.1256-1271.2004.
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ABSTRACT Hyperexpression of the Saccharomyces cerevisiae multidrug ATP-binding cassette (ABC) transporter Pdr5p was driven by the pdr1-3 mutation in the Pdr1p transcriptional regulator in a strain (AD/PDR5+) with deletions of five other ABC-type multidrug efflux pumps. The strain had high-level fluconazole (FLC) resistance (MIC, 600 μg ml−1), and plasma membrane fractions showed oligomycin-sensitive ATPase activity up to fivefold higher than that shown by fractions from an isogenic PDR5-null mutant (FLC MIC, 0.94 μg ml−1). In vitro inhibition of the Pdr5p ATPase activity and chemosensitization of cells to FLC allowed the systematic screening of a 1.8-million-member designer d-octapeptide combinatorial library for surface-active Pdr5p antagonists with modest toxicity against yeast cells. Library deconvolution identified the 4-methoxy-2,3,6-trimethylbenzensulfonyl-substituted d-octapeptide KN20 as a potent Pdr5p ATPase inhibitor (concentration of drug causing 50% inhibition of enzyme activity [IC50], 4 μM) which chemosensitized AD/PDR5+ to FLC, itraconazole, and ketoconazole. It also inhibited the ATPase activity of other ABC transporters, such as Candida albicans Cdr1p (IC50, 30 μM) and Cdr2p (IC50, 2 μM), and chemosensitized clinical isolates of pathogenic Candida species and S. cerevisiae strains that heterologously hyperexpressed either ABC-type multidrug efflux pumps, the C. albicans major facilitator superfamily-type drug transporter BenRp, or the FLC drug target lanosterol 14α-demethylase (Erg11p). Although KN20 also inhibited the S. cerevisiae plasma membrane proton pump Pma1p (IC50, 1 μM), the peptide concentrations required for chemosensitization made yeast cells permeable to rhodamine 6G. KN20 therefore appears to indirectly chemosensitize cells to FLC by a nonlethal permeabilization of the fungal plasma membrane.
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Zheng, Hao, Yuan-Ying Jiang, Yan Wang, Xin-Ming Jia, Tian-Hua Yan, Ping-Hui Gao, Lan Yan, Ling-Huo Jiang, Hui Ji, and Yong-Bing Cao. "TOP2 gene disruption reduces drug susceptibility by increasing intracellular ergosterol biosynthesis in Candida albicans." Journal of Medical Microbiology 59, no. 7 (July 1, 2010): 797–803. http://dx.doi.org/10.1099/jmm.0.018325-0.
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In this study the role of the TOP2 gene in fungal drug susceptibility was investigated by disrupting and overexpressing the gene in Candida albicans. MIC determination and a spot assay showed that a top2Δ/Δ null mutant (strain T2bc) was more resistant to the antifungals tested than the wild-type (strain CAI4). Real-time RT-PCR and rhodamine 6G efflux examination showed that TOP2 did not influence the activity of drug efflux pumps. Sterol analysis with GC/high-resolution MS indicated that the intracellular ergosterol composition of the top2Δ/Δ mutant was significantly increased. Subsequently, fluorescence polarization measurements also revealed that Top2-deprived cells displayed a decrease in membrane fluidity, resulting in enhanced passive diffusion of the drugs. Quantitative real-time RT-PCR analysis further confirmed that the ERG11 gene, an essential gene in ergosterol biosynthesis, was upregulated. These results demonstrate a close relationship between the TOP2 gene and drug susceptibility in C. albicans.
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Ivanov, Marija, Ana Ćirić, and Dejan Stojković. "Emerging Antifungal Targets and Strategies." International Journal of Molecular Sciences 23, no. 5 (March 2, 2022): 2756. http://dx.doi.org/10.3390/ijms23052756.
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Despite abundant research in the field of antifungal drug discovery, fungal infections remain a significant healthcare burden. There is an emerging need for the development of novel antifungals since those currently available are limited and do not completely provide safe and secure protection. Since the current knowledge regarding the physiology of fungal cells and the infection mechanisms is greater than ever, we have the opportunity to use this for the development of novel generations of antifungals. In this review, we selected and summarized recent studies describing agents employing different antifungal mechanisms. These mechanisms include interference with fungal resistance, including impact on the efflux pumps and heat shock protein 90. Additionally, interference with virulence factors, such as biofilms and hyphae; the impact on fungal enzymes, metabolism, mitochondria, and cell wall; and antifungal vaccines are explored. The agents investigated belong to different classes of natural or synthetic molecules with significant attention given also to plant extracts. The efficacy of these antifungals has been studied mainly in vitro with some in vivo, and clinical studies are needed. Nevertheless, there is a large quantity of products employing novel antifungal mechanisms that can be further explored for the development of new generation of antifungals.
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Kostoulias, Xenia, Gerald L. Murray, Gustavo M. Cerqueira, Jason B. Kong, Farkad Bantun, Eleftherios Mylonakis, Chen Ai Khoo, and Anton Y. Peleg. "Impact of a Cross-Kingdom Signaling Molecule of Candida albicans on Acinetobacter baumannii Physiology." Antimicrobial Agents and Chemotherapy 60, no. 1 (October 19, 2015): 161–67. http://dx.doi.org/10.1128/aac.01540-15.
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ABSTRACTMultidrug-resistant (MDR)Acinetobacter baumanniiis an opportunistic human pathogen that has become highly problematic in the clinical environment. Novel therapies are desperately required. To assist in identifying new therapeutic targets, the antagonistic interactions betweenA. baumanniiand the most common human fungal pathogen,Candida albicans, were studied. We have observed that theC. albicansquorum-sensing molecule, farnesol, has cross-kingdom interactions, affecting the viability ofA. baumannii. To gain an understanding of its mechanism, the transcriptional profile ofA. baumanniiexposed to farnesol was examined. Farnesol caused dysregulation of a large number of genes involved in cell membrane biogenesis, multidrug efflux pumps (AcrAB-like and AdeIJK-like), andA. baumanniivirulence traits such as biofilm formation (csuA,csuB, andompA) and motility (pilZandpilH). We also observed a strong induction in genes involved in cell division (minD,minE,ftsK,ftsB, andftsL). These transcriptional data were supported by functional assays showing that farnesol disruptsA. baumanniicell membrane integrity, alters cell morphology, and impairs virulence characteristics such as biofilm formation and twitching motility. Moreover, we showed thatA. baumanniiuses efflux pumps as a defense mechanism against this eukaryotic signaling molecule. Owing to its effects on membrane integrity, farnesol was tested to see if it potentiated the activity of the membrane-acting polymyxin antibiotic colistin. When coadministered, farnesol increased sensitivity to colistin for otherwise resistant strains. These data provide mechanistic understanding of the antagonistic interactions between diverse pathogens and may provide important insights into novel therapeutic strategies.
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Kubová, Zuzana, Tomáš Pagáč, Ján Víglaš, and Petra Olejníková. "Detoxification and adaptation mechanisms of Trichoderma atroviride to antifungal agents." Acta Chimica Slovaca 15, no. 1 (January 1, 2022): 85–96. http://dx.doi.org/10.2478/acs-2022-0010.
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Abstract Filamentous fungi are crucial for recycling of organic material in nature. In natural habitats, they cope with many stress factors and therefore their adaptation ability to various conditions is very high. Trichoderma sp., fungi used in agriculture as biocontrol agent, are exposed to a variety of toxic molecules including pesticides and fungicides. They have to fight with toxic molecules using stress adaptation mechanisms known as the stress response. Adaptation of fungi to stress, especially to chemical stress, is not well studied in environmental fungal strains. Moreover, the adaptation process presents a risk of resistance mechanism induction to antifungal agents. Such resistant strains could be spread in the environment. This work aims to contribute to the knowledge of the adaptation process spread throughout the fungal kingdom. Transcriptional response of ABC transporters, the main detoxification efflux pumps of subfamily B and G in presence of antifungal agents, is shown. On the other hand, as azoles are the most commonly used antifungal structures in clinical practice and agriculture, changes in important fungal ergosterol biosynthesis genes as a result of their exposure to various azoles structure are highlighted.
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Rosam, Katharina, Brian C. Monk, and Michaela Lackner. "Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens." Journal of Fungi 7, no. 1 (December 22, 2020): 1. http://dx.doi.org/10.3390/jof7010001.
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The fungal cytochrome P450 enzyme sterol 14α-demethylase (SDM) is a key enzyme in the ergosterol biosynthesis pathway. The binding of azoles to the active site of SDM results in a depletion of ergosterol, the accumulation of toxic intermediates and growth inhibition. The prevalence of azole-resistant strains and fungi is increasing in both agriculture and medicine. This can lead to major yield loss during food production and therapeutic failure in medical settings. Diverse mechanisms are responsible for azole resistance. They include amino acid (AA) substitutions in SDM and overexpression of SDM and/or efflux pumps. This review considers AA affecting the ligand-binding pocket of SDMs with a primary focus on substitutions that affect interactions between the active site and the substrate and inhibitory ligands. Some of these interactions are particularly important for the binding of short-tailed azoles (e.g., voriconazole). We highlight the occurrence throughout the fungal kingdom of some key AA substitutions. Elucidation of the role of these AAs and their substitutions may assist drug design in overcoming some common forms of innate and acquired azole resistance.
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Dittrich, Torsten, Nils Hanekop, Nacera Infed, Lutz Schmitt, and Manfred Braun. "Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance." Beilstein Journal of Organic Chemistry 8 (October 5, 2012): 1700–1704. http://dx.doi.org/10.3762/bjoc.8.193.
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The inhibition of ABC (ATP binding cassette) transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.
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Dinić, Jelena, Ana Podolski-Renić, Marko Jeremić, and Milica Pešić. "Potential of Natural-Based Anticancer Compounds for P-Glycoprotein Inhibition." Current Pharmaceutical Design 24, no. 36 (February 15, 2019): 4334–54. http://dx.doi.org/10.2174/1381612825666190112164211.
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Medicinal value of natural products comes from symbiotic and competitive evolution in Earth’s complex biosphere. Billions of years of co-evolutionary interactions among millions of species have produced a large repertoire of defense molecules effective in fighting bacteria, viral, and fungal pathogens. Each species contains millions of different and useful molecules and new research technologies enabled the screening of molecules and complex mixtures from diverse biological sources. Traditional use of plants and other species led to the discovery of many bioactive compounds with various properties. In the last four decades, a large number of them were evaluated for their potential to treat cancer. Penetration of drugs into the cancer cell is necessary for their lethal pharmacological effect through interaction with intracellular target molecules. Increased activity of membrane efflux pumps reduces the intracellular drug accumulation, thereby preventing drug-target interactions. The discovery of the efflux transporter P-glycoprotein (P-gp) in multidrug resistant (MDR) cancer cells prompted the efforts in overcoming drug resistance by P-gp inhibition. The search for nontoxic anticancer agents from natural sources able to overcome MDR has been imperative in the field of drug design and discovery. Herein, we review various natural compounds from diverse sources emphasizing their potential to inhibit P-gp activity and/or expression.
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White, Theodore C., Kieren A. Marr, and Raleigh A. Bowden. "Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance." Clinical Microbiology Reviews 11, no. 2 (April 1, 1998): 382–402. http://dx.doi.org/10.1128/cmr.11.2.382.
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SUMMARY In the past decade, the frequency of diagnosed fungal infections has risen sharply due to several factors, including the increase in the number of immunosuppressed patients resulting from the AIDS epidemic and treatments during and after organ and bone marrow transplants. Linked with the increase in fungal infections is a recent increase in the frequency with which these infections are recalcitrant to standard antifungal therapy. This review summarizes the factors that contribute to antifungal drug resistance on three levels: (i) clinical factors that result in the inability to successfully treat refractory disease; (ii) cellular factors associated with a resistant fungal strain; and (iii) molecular factors that are ultimately responsible for the resistance phenotype in the cell. Many of the clinical factors that contribute to resistance are associated with the immune status of the patient, with the pharmacology of the drugs, or with the degree or type of fungal infection present. At a cellular level, antifungal drug resistance can be the result of replacement of a susceptible strain with a more resistant strain or species or the alteration of an endogenous strain (by mutation or gene expression) to a resistant phenotype. The molecular mechanisms of resistance that have been identified to date in Candida albicans include overexpression of two types of efflux pumps, overexpression or mutation of the target enzyme, and alteration of other enzymes in the same biosynthetic pathway as the target enzyme. Since the study of antifungal drug resistance is relatively new, other factors that may also contribute to resistance are discussed.
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Lamping, Erwin, Brian C. Monk, Kyoko Niimi, Ann R. Holmes, Sarah Tsao, Koichi Tanabe, Masakazu Niimi, Yoshimasa Uehara, and Richard D. Cannon. "Characterization of Three Classes of Membrane Proteins Involved in Fungal Azole Resistance by Functional Hyperexpression in Saccharomyces cerevisiae." Eukaryotic Cell 6, no. 7 (May 18, 2007): 1150–65. http://dx.doi.org/10.1128/ec.00091-07.
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ABSTRACT The study of eukaryotic membrane proteins has been hampered by a paucity of systems that achieve consistent high-level functional protein expression. We report the use of a modified membrane protein hyperexpression system to characterize three classes of fungal membrane proteins (ABC transporters Pdr5p, CaCdr1p, CaCdr2p, CgCdr1p, CgPdh1p, CkAbc1p, and CneMdr1p, the major facilitator superfamily transporter CaMdr1p, and the cytochrome P450 enzyme CaErg11p) that contribute to the drug resistance phenotypes of five pathogenic fungi and to express human P glycoprotein (HsAbcb1p). The hyperexpression system consists of a set of plasmids that direct the stable integration of a single copy of the expression cassette at the chromosomal PDR5 locus of a modified host Saccharomyces cerevisiae strain, ADΔ. Overexpression of heterologous proteins at levels of up to 29% of plasma membrane protein was achieved. Membrane proteins were expressed with or without green fluorescent protein (GFP), monomeric red fluorescent protein, His, FLAG/His, Cys, or His/Cys tags. Most GFP-tagged proteins tested were correctly trafficked within the cell, and His-tagged proteins could be affinity purified. Kinetic analysis of ABC transporters indicated that the apparent K m value and the V max value of ATPase activities were not significantly affected by the addition of His tags. The efflux properties of seven fungal drug pumps were characterized by their substrate specificities and their unique patterns of inhibition by eight xenobiotics that chemosensitized S. cerevisiae strains overexpressing ABC drug pumps to fluconazole. The modified hyperexpression system has wide application for the study of eukaryotic membrane proteins and could also be used in the pharmaceutical industry for drug screening.
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Rao, Harinash, Sulin Choo, Sri Raja Rajeswari Mahalingam, Diajeng Sekar Adisuri, Priya Madhavan, Abdah Md. Akim, and Pei Pei Chong. "Approaches for Mitigating Microbial Biofilm-Related Drug Resistance: A Focus on Micro- and Nanotechnologies." Molecules 26, no. 7 (March 26, 2021): 1870. http://dx.doi.org/10.3390/molecules26071870.
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Biofilms play an essential role in chronic and healthcare-associated infections and are more resistant to antimicrobials compared to their planktonic counterparts due to their (1) physiological state, (2) cell density, (3) quorum sensing abilities, (4) presence of extracellular matrix, (5) upregulation of drug efflux pumps, (6) point mutation and overexpression of resistance genes, and (7) presence of persister cells. The genes involved and their implications in antimicrobial resistance are well defined for bacterial biofilms but are understudied in fungal biofilms. Potential therapeutics for biofilm mitigation that have been reported include (1) antimicrobial photodynamic therapy, (2) antimicrobial lock therapy, (3) antimicrobial peptides, (4) electrical methods, and (5) antimicrobial coatings. These approaches exhibit promising characteristics for addressing the impending crisis of antimicrobial resistance (AMR). Recently, advances in the micro- and nanotechnology field have propelled the development of novel biomaterials and approaches to combat biofilms either independently, in combination or as antimicrobial delivery systems. In this review, we will summarize the general principles of clinically important microbial biofilm formation with a focus on fungal biofilms. We will delve into the details of some novel micro- and nanotechnology approaches that have been developed to combat biofilms and the possibility of utilizing them in a clinical setting.
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Ivanov, Marija, Abhilash Kannan, Dejan S. Stojković, Jasmina Glamočlija, Ricardo C. Calhelha, Isabel C. F. R. Ferreira, Dominique Sanglard, and Marina Soković. "Flavones, Flavonols, and Glycosylated Derivatives—Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity." Pharmaceuticals 14, no. 1 (December 30, 2020): 27. http://dx.doi.org/10.3390/ph14010027.
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Due to the high incidence of fungal infections worldwide, there is an increasing demand for the development of novel therapeutic approaches. A wide range of natural products has been extensively studied, with considerable focus on flavonoids. The antifungal capacity of selected flavones (luteolin, apigenin), flavonols (quercetin), and their glycosylated derivatives (quercitrin, isoquercitrin, rutin, and apigetrin) along with their impact on genes encoding efflux pumps (CDR1) and ergosterol biosynthesis enzyme (ERG11) has been the subject of this study. Cytotoxicity of flavonoids towards primary liver cells has also been addressed. Luteolin, quercitrin, isoquercitrin, and rutin inhibited growth of Candida albicans with the minimal inhibitory concentration of 37.5 µg/mL. The application of isoquercitrin has reduced C. albicans biofilm establishing capacities for 76%, and hyphal formation by yeast. In vitro treatment with apigenin, apigetrin, and quercitrin has downregulated CDR1. Contrary to rutin and apigenin, isoquercitrin has upregulated ERG11. Except apigetrin and quercitrin (90 µg/mL and 73 µg/mL, respectively inhibited 50% of the net cell growth), the examined flavonoids did not exhibit cytotoxicity. The reduction of both fungal virulence and expression of antifungal resistance-linked genes was the most pronounced for apigenin and apigetrin; these results indicate flavonoids’ indispensable capacity for further development as part of an anticandidal therapy or prevention strategy.
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Hu, Mengjun, and Shuning Chen. "Non-Target Site Mechanisms of Fungicide Resistance in Crop Pathogens: A Review." Microorganisms 9, no. 3 (February 27, 2021): 502. http://dx.doi.org/10.3390/microorganisms9030502.
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The rapid emergence of resistance in plant pathogens to the limited number of chemical classes of fungicides challenges sustainability and profitability of crop production worldwide. Understanding mechanisms underlying fungicide resistance facilitates monitoring of resistant populations at large-scale, and can guide and accelerate the development of novel fungicides. A majority of modern fungicides act to disrupt a biochemical function via binding a specific target protein in the pathway. While target-site based mechanisms such as alternation and overexpression of target genes have been commonly found to confer resistance across many fungal species, it is not uncommon to encounter resistant phenotypes without altered or overexpressed target sites. However, such non-target site mechanisms are relatively understudied, due in part to the complexity of the fungal genome network. This type of resistance can oftentimes be transient and noninheritable, further hindering research efforts. In this review, we focused on crop pathogens and summarized reported mechanisms of resistance that are otherwise related to target-sites, including increased activity of efflux pumps, metabolic circumvention, detoxification, standing genetic variations, regulation of stress response pathways, and single nucleotide polymorphisms (SNPs) or mutations. In addition, novel mechanisms of drug resistance recently characterized in human pathogens are reviewed in the context of nontarget-directed resistance.
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Kabir, M. Anaul, and Zulfiqar Ahmad. "Candida Infections and Their Prevention." ISRN Preventive Medicine 2013 (November 4, 2013): 1–13. http://dx.doi.org/10.5402/2013/763628.
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Infections caused by Candida species have been increased dramatically worldwide due to the increase in immunocompromised patients. For the prevention and cure of candidiasis, several strategies have been adopted at clinical level. Candida infected patients are commonly treated with a variety of antifungal drugs such as fluconazole, amphotericin B, nystatin, and flucytosine. Moreover, early detection and speciation of the fungal agents will play a crucial role for administering appropriate drugs for antifungal therapy. Many modern technologies like MALDI-TOF-MS, real-time PCR, and DNA microarray are being applied for accurate and fast detection of the strains. However, during prolonged use of these drugs, many fungal pathogens become resistant and antifungal therapy suffers. In this regard, combination of two or more antifungal drugs is thought to be an alternative to counter the rising drug resistance. Also, many inhibitors of efflux pumps have been designed and tested in different models to effectively treat candidiasis. However, most of the synthetic drugs have side effects and biomedicines like antibodies and polysaccharide-peptide conjugates could be better alternatives and safe options to prevent and cure the diseases. Furthermore, availability of genome sequences of Candida albicans and other non-albicans strains has made it feasible to analyze the genes for their roles in adherence, penetration, and establishment of diseases. Understanding the biology of Candida species by applying different modern and advanced technology will definitely help us in preventing and curing the diseases caused by fungal pathogens.
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Neves-Junior, Athayde, Ana Carolina Cartágenes-Pinto, Débora A. S. Rocha, Leandro F. Reis de Sá, Maria de Lourdes Junqueira, and Antonio Ferreira-Pereira. "Prevalence and Fluconazole Susceptibility Profile of Candida spp. Clinical Isolates in a Brazilian Tertiary Hospital in Minas Gerais, Brazil." Anais da Academia Brasileira de Ciências 87, no. 2 suppl (August 25, 2015): 1349–59. http://dx.doi.org/10.1590/0001-3765201520140717.
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Candidiasis has become an important concern for clinical practice, especially with the increasing incidence of immunocompromised patients. In this scenario, the development resistance to fluconazole presents a challenge for treating these opportunistic infections. The aim of this study was to evaluate some epidemiology features of Candidainfections in a Brazilian University Hospital using data, previously unavailable. We observed that 44% of the 93 clinical isolates tested, belonged to Candida albicansspecies and 56% belonged to non-Candida albicansspecies (mainly Candida tropicalis and Candida glabrata). Most strains were isolated from urine samples where C. albicans was predominantly detected. 29 strains presented a fluconazole resistance phenotype and of these, 22 were chemosensitised by FK506, a classical inhibitor of ABC transporters related to azoles resistance. These data suggest the probable role of efflux pumps in this resistance phenotype. Our study highlights the need for developing effective control measures for fungal infections, rational use of antifungal drugs and development of new molecules able to abrogate the active transport of antifungals.
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Costa-de-Oliveira, Sofia, and Acácio G. Rodrigues. "Candida albicans Antifungal Resistance and Tolerance in Bloodstream Infections: The Triad Yeast-Host-Antifungal." Microorganisms 8, no. 2 (January 22, 2020): 154. http://dx.doi.org/10.3390/microorganisms8020154.
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Candida albicans represents the most frequent isolated yeast from bloodstream infections. Despite the remarkable progress in diagnostic and therapeutic approaches, these infections continue to be a critical challenge in intensive care units worldwide. The economic cost of bloodstream fungal infections and its associated mortality, especially in debilitated patients, remains unacceptably high. Candida albicans is a highly adaptable microorganism, being able to develop resistance following prolonged exposure to antifungals. Formation of biofilms, which diminish the accessibility of the antifungal, selection of spontaneous mutations that increase expression or decreased susceptibility of the target, altered chromosome abnormalities, overexpression of multidrug efflux pumps and the ability to escape host immune defenses are some of the factors that can contribute to antifungal tolerance and resistance. The knowledge of the antifungal resistance mechanisms can allow the design of alternative therapeutically options in order to modulate or revert the resistance. We have focused this review on the main factors that are involved in antifungal resistance and tolerance in patients with C. albicans bloodstream infections.
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Jesus, Ana, Fernando Durães, Nikoletta Szemerédi, Joana Freitas-Silva, Paulo Martins da Costa, Eugénia Pinto, Madalena Pinto, Gabriella Spengler, Emília Sousa, and Honorina Cidade. "BDDE-Inspired Chalcone Derivatives to Fight Bacterial and Fungal Infections." Marine Drugs 20, no. 5 (May 8, 2022): 315. http://dx.doi.org/10.3390/md20050315.
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The growing number of infectious diseases around the world threatens the effective response of antibiotics, contributing to the increase in antibiotic resistance seen as a global health problem. Currently, one of the main challenges in antimicrobial drug discovery is the search for new compounds that not only exhibit antimicrobial activity, but can also potentiate the antimicrobial activity and revert antibiotics’ resistance, through the interference with several mechanisms, including the inhibition of efflux pumps (EPs) and biofilm formation. Inspired by macroalgae brominated bromophenol BDDE with antimicrobial activity, a series of 18 chalcone derivatives, including seven chalcones (9–15), six dihydrochalcones (16–18, and 22–24) and five diarylpropanes (19–21, and 25 and 26), was prepared and evaluated for its antimicrobial activity and potential to fight antibiotic resistance. Among them, chalcones 13 and 14 showed promising antifungal activity against the dermatophyte clinical strain of Trichophyton rubrum, and all compounds reversed the resistance to vancomycin in Enterococcus faecalis B3/101, with 9, 14, and 24 able to cause a four-fold decrease in the MIC of vancomycin against this strain. Compounds 17–24 displayed inhibition of EPs and the formation of biofilm by S. aureus 272123, suggesting that these compounds are inhibiting the EPs responsible for the extrusion of molecules involved in biofilm-related mechanisms. Interestingly, compounds 17–24 did not show cytotoxicity in mouse embryonic fibroblast cell lines (NIH/3T3). Overall, the results obtained suggest the potential of dihydrochalcones 16–18 and 22–24, and diarylpropanes 19–21, 25 and 26, as hits for bacterial EPs inhibition, as they are effective in the inhibition of EPs, but present other features that are important in this matter, such as the lack of antibacterial activity and cytotoxicity.
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Awad, Andy, Pamela El Khoury, Geovanni Geukgeuzian, and Roy A. Khalaf. "Cell Wall Proteome Profiling of a Candida albicans Fluconazole-Resistant Strain from a Lebanese Hospital Patient Using Tandem Mass Spectrometry—A Pilot Study." Microorganisms 9, no. 6 (May 28, 2021): 1161. http://dx.doi.org/10.3390/microorganisms9061161.
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Candida albicans is an opportunistic pathogenic fungus responsible for high mortality rates in immunocompromised individuals. Azole drugs such as fluconazole are the first line of therapy in fungal infection treatment. However, resistance to azole treatment is on the rise. Here, we employ a tandem mass spectrometry approach coupled with a bioinformatics approach to identify cell wall proteins present in a fluconazole-resistant hospital isolate upon drug exposure. The isolate was previously shown to have an increase in cell membrane ergosterol and cell wall chitin, alongside an increase in adhesion, but slightly attenuated in virulence. We identified 50 cell wall proteins involved in ergosterol biosynthesis such as Erg11, and Erg6, efflux pumps such as Mdr1 and Cdr1, adhesion proteins such as Als1, and Pga60, chitin deposition such as Cht4, and Crh11, and virulence related genes including Sap5 and Lip9. Candidial proteins identified in this study go a long way in explaining the observed phenotypes. Our pilot study opens the way for a future large-scale analysis to identify novel proteins involved in drug-resistance mechanisms.
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Silva, Suéllen Pedrosa da, Clarice Barbosa Lucena da Costa, José Dayvid Ferreira da Silva, Robson Raion de Vasconcelos Alves, Guilherme Antonio de Souza Silva, Anderson Felipe Soares de Freitas, Caio César da Silva Guedes, Amanda de Oliveira Marinho, Patrícia Maria Guedes Paiva, and Thiago Henrique Napoleão. "Resistance mechanisms of Cryptococcus spp. and plant compounds as tools to combat them." Research, Society and Development 10, no. 2 (February 24, 2021): e57810212819. http://dx.doi.org/10.33448/rsd-v10i2.12819.
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Cryptococcus is a genus of dimorphic basidiomycete fungi found in the form of yeasts and filaments. Cryptococcosis has as main etiological agents the species Cryptococcus neoformans and Cryptococcus gattii. This disease is considered a public health problem and has becoming more alarming because of the limitations of antimicrobials available to its treatment, in addition to an increase in reports of fungal resistance. In this sense, the present review sought to survey information on the resistance mechanisms of Cryptococcus spp. against the main drugs used in cryptococcosis therapy as well as on the antimicrobial activities of plants against these fungi. Studies have reported that several mechanisms may be involved in fungal resistance to drugs including drug inactivation by enzymes, expression of efflux pumps and others drug transporters, as well as changes in the drug target and/or implementation of alternative metabolic pathways. As an alternative to conventional antimicrobials, substances and molecules extracted from plants have demonstrated potential for controlling these pathogens. These phytochemicals can trigger the inhibition and/or death of Cryptococcus through morphological changes on fungi cells, inhibition of ergosterol synthesis, cell leakage, capsular decrease, interference in cell division, reduction of activity of several enzymes such as laccase and urease, inhibition of biofilm formation, among others. In this sense, plants are an important source of bioactive compounds with antimicrobial activity that can be studied in the search for new drugs that are increasingly effective, specific and less toxic in the control of cryptococcosis.
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Buurman, Ed T., April E. Blodgett, Kenneth G. Hull, and Daniel Carcanague. "Pyridines and Pyrimidines Mediating Activity against an Efflux-Negative Strain of Candida albicans through Putative Inhibition of Lanosterol Demethylase." Antimicrobial Agents and Chemotherapy 48, no. 1 (January 2004): 313–18. http://dx.doi.org/10.1128/aac.48.1.313-318.2004.
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ABSTRACT The first step in ergosterol biosynthesis in Saccharomyces cerevisiae consists of the condensation of two acetyl coenzyme A (acetyl-CoA) moieties by acetoacetyl-CoA thiolase, encoded by ERG10. The inhibition of the sterol pathway results in feedback activation of ERG10 transcription. A cell-based reporter assay, in which increased ERG10 transcription results in elevated specific β-galactosidase activity, was used to find novel inhibitors of ergosterol biosynthesis that could serve as chemical starting points for the development of novel antifungal agents. A class of pyridines and pyrimidines identified in this way had no detectable activity against the major fungal pathogen Candida albicans (MICs > 64 μg · ml−1). However, a strain of C. albicans lacking the Cdr1p and Cdr2p efflux pumps was sensitive to the compounds (with MICs ranging from 2 to 64 μg · ml−1), suggesting that they are efficiently removed from wild-type cells. Quantitative analysis of sterol intermediates that accumulated during growth inhibition revealed the accumulation of lanosterol at the expense of ergosterol. Furthermore, a clear correlation was found between the 50% inhibitory concentration at which the sterol profile was altered and the antifungal activity, measured as the MIC. This finding strongly suggests that the inhibition of growth was caused by a reduction in ergosterol synthesis. The compounds described here are a novel class of antifungal pyridines and pyrimidines and the first pyri(mi)dines to be shown to putatively mediate their antifungal activity against C. albicans via lanosterol demethylase.
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Boren, Karen, AliceAnn Crown, and Richard Carlson. "Multidrug and Pan-Antibiotic Resistance—The Role of Antimicrobial and Synergistic Essential Oils: A Review." Natural Product Communications 15, no. 10 (October 2020): 1934578X2096259. http://dx.doi.org/10.1177/1934578x20962595.
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Bacterial resistance to antibiotics continues to be a grave threat to human health. Because antibiotics are no longer a lucrative market for pharmaceutical companies, the development of new antibiotics has slowed to a crawl. The World Health Organization reported that the 8 new bacterial agents approved since July 2017 had limited clinical benefits. While a cohort of biopharmaceutical companies recently announced plans to develop 2-4 new antibiotics by 2030, we needn’t wait a decade to find innovative antibiotic candidates. Essential oils (EOs) have long been known as antibacterial agents with wide-ranging arsenals. Many are able to penetrate the bacterial membrane and may also be effective against bacterial defenses such as biofilms, efflux pumps, and quorum sensing. EOs have been documented to fight drug-resistant bacteria alone and/or combined with antibiotics. This review will summarize research showing the significant role of EOs as nonconventional regimens against the worldwide spread of antibiotic-resistant pathogens. The authors conducted a 4-year search of the US National Library of Medicine (PubMed) for relevant EO studies against methicillin-resistant Staphylococcus aureus, multidrug-resistant (MDR) Escherichia coli, EO combinations/synergy with antibiotics, against MDR fungal infections, showing the ability to permeate bacterial membranes, and against the bacterial defenses listed above. EOs are readily available and are a needed addition to the arsenal against resistant pathogens.
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Renau, T. E., and R. C. Lemoine. "Efflux pump inhibitors to address bacterial and fungal resistance." Drugs of the Future 26, no. 12 (2001): 1171. http://dx.doi.org/10.1358/dof.2001.026.12.644122.
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Park, Yang-Nim, and Joachim Morschhäuser. "Tetracycline-Inducible Gene Expression and Gene Deletion in Candida albicans." Eukaryotic Cell 4, no. 8 (August 2005): 1328–42. http://dx.doi.org/10.1128/ec.4.8.1328-1342.2005.
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ABSTRACT The genetic analysis of Candida albicans, the major fungal pathogen of humans, is hampered by its diploid genome, the absence of a normal sexual cycle, and a nonstandard codon usage. Although effective methods to study gene function have been developed in the past years, systems to control gene expression in C. albicans are limited. We have established a system that allows induction of gene expression in C. albicans by the addition of tetracycline (Tet). By fusing genetically modified versions of the reverse Tet repressor from Escherichia coli and the transcription activation domain of the Gal4 protein from Saccharomyces cerevisiae, a C. albicans-adapted reverse Tet-dependent transactivator (rtTA) was created that was expressed from the constitutive ADH1 or the opaque-specific OP4 promoter. To monitor Tet-inducible gene expression, the caGFP reporter gene was placed under the control of a Tet-dependent promoter, obtained by fusing a minimal promoter from C. albicans to seven copies of the Tet operator sequence. Fluorescence of the cells demonstrated that gene expression could be efficiently induced by the addition of doxycycline in yeast, hyphal, and opaque cells of C. albicans. The Tet-inducible gene expression system was then used to manipulate the behavior of the various growth forms of C. albicans. Tet-induced expression of a dominant-negative CDC42 allele resulted in growth arrest as large, multinucleate cells. Filamentous growth was efficiently inhibited under all tested hyphal-growth-promoting conditions by Tet-inducible expression of the NRG1 repressor. Tet-induced expression of the MTL a 1 gene in opaque cells of an MTLα strain forced the cells to switch to the white phase, whereas Tet-induced expression of the MTL a 2 transcription factor induced shmooing. When the ecaFLP gene, encoding the site-specific recombinase FLP, was placed under the control of the Tet-dependent promoter, Tet-inducible deletion of genes which were flanked by the FLP target sequences was achieved with high efficiency to generate conditional null mutants. In combination with the dominant selection marker caSAT1, the Tet-inducible gene expression system was also applied in C. albicans wild-type strains, including drug-resistant clinical isolates that overexpressed the MDR1, CDR1, and CDR2 multidrug efflux pumps. This system, therefore, allows a growth medium-independent, Tet-inducible expression and deletion of genes in C. albicans and provides a convenient, versatile new tool to study gene function and manipulate cellular behavior in this model pathogenic fungus.
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Ramage, Gordon, Ranjith Rajendran, Leighann Sherry, and Craig Williams. "Fungal Biofilm Resistance." International Journal of Microbiology 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/528521.
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Fungal biofilm infections have become increasingly recognised as a significant clinical problem. One of the major reasons behind this is the impact that these have upon treatment, as antifungal therapy often fails and surgical intervention is required. This places a large financial burden on health care providers. This paper aims to illustrate the importance of fungal biofilms, particularlyCandida albicans, and discusses some of the key fungal biofilm resistance mechanisms that include, extracellular matrix (ECM), efflux pump activity, persisters, cell density, overexpression of drug targets, stress responses, and the general physiology of the cell. The paper demonstrates the multifaceted nature of fungal biofilm resistance, which encompasses some of the newest data and ideas in the field.
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Costa-de-Oliveira, Sofia, Isabel M. Miranda, Ana Silva-Dias, Ana P. Silva, Acácio G. Rodrigues, and Cidália Pina-Vaz. "Ibuprofen Potentiates theIn VivoAntifungal Activity of Fluconazole against Candida albicans Murine Infection." Antimicrobial Agents and Chemotherapy 59, no. 7 (April 6, 2015): 4289–92. http://dx.doi.org/10.1128/aac.05056-14.
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ABSTRACTCandida albicansis the most prevalent cause of fungemia worldwide. Its ability to develop resistance in patients receiving azole antifungal therapy is well documented. In a murine model of systemic infection, we show that ibuprofen potentiates fluconazole antifungal activity against a fluconazole-resistant strain, drastically reducing the fungal burden and morbidity. The therapeutic combination of fluconazole with ibuprofen may constitute a new approach for the management of antifungal therapeutics to reverse the resistance conferred by efflux pump overexpression.
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Watkins, William J., Lee Chong, Aesop Cho, Ramona Hilgenkamp, Maria Ludwikow, Negar Garizi, Nadeem Iqbal, et al. "Quinazolinone fungal efflux pump inhibitors. Part 3: (N-methyl)piperazine variants and pharmacokinetic optimization." Bioorganic & Medicinal Chemistry Letters 17, no. 10 (May 2007): 2802–6. http://dx.doi.org/10.1016/j.bmcl.2007.02.047.
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Alqahtani, Moneerah J., Engy Elekhnawy, Walaa A. Negm, Sebaey Mahgoub, and Ismail A. Hussein. "Encephalartos villosus Lem. Displays a Strong In Vivo and In Vitro Antifungal Potential against Candida glabrata Clinical Isolates." Journal of Fungi 8, no. 5 (May 18, 2022): 521. http://dx.doi.org/10.3390/jof8050521.
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Recently, Candida glabrata has been recognized as one of the most common fungal species that is highly associated with invasive candidiasis. Its spread could be attributed to its increasing resistance to antifungal drugs. Thus, there is a high need for safer and more efficient therapeutic alternatives such as plant extracts. Here, we investigated the antifungal potential of Encephalartos villosus leaves methanol extract (EVME) against C. glabrata clinical isolates. Tentative phytochemical identification of 51 metabolites was conducted in EVME using LC–MS/MS. EVME demonstrated antifungal activity with minimum inhibitory concentrations that ranged from 32 to 256 µg/mL. The mechanism of the antifungal action was studied by investigating the impact of EVME on nucleotide leakage. Additionally, a sorbitol bioassay was performed, and we found that EVME affected the fungal cell wall. In addition, the effect of EVME was elucidated on the efflux activity of C. glabrata isolates using acridine orange assay and quantitative real-time PCR. EVME resulted in downregulation of the expression of the efflux pump genes CDR1, CDR2, and ERG11 in the tested isolates with percentages of 33.33%, 41.67%, and 33.33%, respectively. Moreover, we investigated the in vivo antifungal activity of EVME using a murine model with systemic infection. The fungal burden was determined in the kidney tissues. Histological and immunohistochemical studies were carried out to investigate the effect of EVME. We noticed that EVME reduced the congestion of the glomeruli and tubules of the kidney tissues of the rats infected with C. glabrata. Furthermore, it decreased both the proinflammatory cytokine tumor necrosis factor-alpha and the abnormal collagen fibers. Our results reveal, for the first time, the potential in vitro (by inhibition of the efflux activity) and in vivo (by decreasing the congestion and inflammation of the kidney tissues) antifungal activity of EVME against C. glabrata isolates.
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Piecuch, Agata, and Ewa Obłąk. "Yeast ABC proteins involved in multidrug resistance." Cellular and Molecular Biology Letters 19, no. 1 (January 1, 2014): 1–22. http://dx.doi.org/10.2478/s11658-013-0111-2.
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AbstractPleiotropic drug resistance is a complex phenomenon that involves many proteins that together create a network. One of the common mechanisms of multidrug resistance in eukaryotic cells is the active efflux of a broad range of xenobiotics through ATP-binding cassette (ABC) transporters. Saccharomyces cerevisiae is often used as a model to study such activity because of the functional and structural similarities of its ABC transporters to mammalian ones. Numerous ABC transporters are found in humans and some are associated with the resistance of tumors to chemotherapeutics. Efflux pump modulators that change the activity of ABC proteins are the most promising candidate drugs to overcome such resistance. These modulators can be chemically synthesized or isolated from natural sources (e.g., plant alkaloids) and might also be used in the treatment of fungal infections. There are several generations of synthetic modulators that differ in specificity, toxicity and effectiveness, and are often used for other clinical effects.
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Prasad, Rajendra, Monika Sharma, and Manpreet Kaur Rawal. "Functionally Relevant Residues of Cdr1p: A Multidrug ABC Transporter of Human Pathogenic Candida albicans." Journal of Amino Acids 2011 (April 27, 2011): 1–12. http://dx.doi.org/10.4061/2011/531412.
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Reduced intracellular accumulation of drugs (due to rapid efflux) mediated by the efflux pump proteins belonging to ABC (ATP Binding Cassette) and MFS (Major Facilitators) superfamily is one of the most common strategies adopted by multidrug resistance (MDR) pathogenic yeasts. To combat MDR, it is essential to understand the structure and function of these transporters so that inhibitors/modulators to these can be developed. The sequence alignments of the ABC transporters reveal selective divergence within much conserved domains of Nucleotide-Binding Domains (NBDs) which is unique to all fungal transporters. Recently, the role of conserved but divergent residues of Candida Drug Resistance 1 (CDR1), an ABC drug transporter of human pathogenic Candida albicans, has been examined with regard to ATP binding and hydrolysis. In this paper, we focus on some of the recent advances on the relevance of divergent and conserved amino acids of CaCdr1p and also discuss as to how drug interacts with Trans Membrane Domains (TMDs) residues for its extrusion from MDR cells.
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Schubert, Sabrina, Katherine S. Barker, Sadri Znaidi, Sabrina Schneider, Franziska Dierolf, Nico Dunkel, Malika Aïd, et al. "Regulation of Efflux Pump Expression and Drug Resistance by the Transcription Factors Mrr1, Upc2, and Cap1 in Candida albicans." Antimicrobial Agents and Chemotherapy 55, no. 5 (March 14, 2011): 2212–23. http://dx.doi.org/10.1128/aac.01343-10.
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ABSTRACTConstitutive overexpression of the Mdr1 efflux pump is an important mechanism of acquired drug resistance in the yeastCandida albicans. The zinc cluster transcription factor Mrr1 is a central regulator ofMDR1expression, but other transcription factors have also been implicated inMDR1regulation. To better understand howMDR1-mediated drug resistance is achieved in this fungal pathogen, we studied the interdependence of Mrr1 and two otherMDR1regulators, Upc2 and Cap1, in the control ofMDR1expression. A mutated, constitutively active Mrr1 could upregulateMDR1and confer drug resistance in the absence of Upc2 or Cap1. On the other hand, Upc2 containing a gain-of-function mutation only slightly activated theMDR1promoter, and this activation depended on the presence of a functionalMRR1gene. In contrast, a C-terminally truncated, activated form of Cap1 could upregulateMDR1in a partially Mrr1-independent fashion. The induction ofMDR1expression by toxic chemicals occurred independently of Upc2 but required the presence of Mrr1 and also partially depended on Cap1. Transcriptional profiling andin vivoDNA binding studies showed that a constitutively active Mrr1 binds to and upregulates most of its direct target genes in the presence or absence of Cap1. Therefore, Mrr1 and Cap1 cooperate in the environmental induction ofMDR1expression in wild-typeC. albicans, but gain-of-function mutations in either of the two transcription factors can independently mediate efflux pump overexpression and drug resistance.
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Gonçalves, A. Pedro, Kevin McCluskey, N. Louise Glass, and Arnaldo Videira. "The Fungal Cell Death Regulator czt-1 Is Allelic to acr-3." Journal of Fungi 5, no. 4 (December 6, 2019): 114. http://dx.doi.org/10.3390/jof5040114.
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Fungal infections have far-reaching implications that range from severe human disease to a panoply of disruptive agricultural and ecological effects, making it imperative to identify and understand the molecular pathways governing the response to antifungal compounds. In this context, CZT-1 (cell death-activated zinc cluster transcription factor) functions as a master regulator of cell death and drug susceptibility in Neurospora crassa. Here we provide evidence indicating that czt-1 is allelic to acr-3, a previously described locus that we now found to harbor a point mutation in its coding sequence. This nonsynonymous amino acid substitution in a low complexity region of CZT-1/ACR-3 caused a robust gain-of-function that led to reduced sensitivity to acriflavine and staurosporine, and increased expression of the drug efflux pump abc-3. Thus, accumulating evidence shows that CZT-1 is an important broad regulator of the cellular response to various antifungal compounds that appear to share common molecular targets.
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Guo, X. L., P. Leng, Y. Yang, L. G. Yu, and H. X. Lou. "Plagiochin E, a botanic-derived phenolic compound, reverses fungal resistance to fluconazole relating to the efflux pump." Journal of Applied Microbiology 104, no. 3 (March 2008): 831–38. http://dx.doi.org/10.1111/j.1365-2672.2007.03617.x.
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Sastré-Velásquez, Luis Enrique, Alex Dallemulle, Alexander Kühbacher, Clara Baldin, Laura Alcazar-Fuoli, Anna Niedrig, Christoph Müller, and Fabio Gsaller. "The fungal expel of 5-fluorocytosine derived fluoropyrimidines mitigates its antifungal activity and generates a cytotoxic environment." PLOS Pathogens 18, no. 12 (December 27, 2022): e1011066. http://dx.doi.org/10.1371/journal.ppat.1011066.
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Invasive aspergillosis remains one of the most devastating fungal diseases and is predominantly linked to infections caused by the opportunistic human mold pathogen Aspergillus fumigatus. Major treatment regimens for the disease comprise the administration of antifungals belonging to the azole, polyene and echinocandin drug class. The prodrug 5-fluorocytosine (5FC), which is the only representative of a fourth class, the nucleobase analogs, shows unsatisfactory in vitro activities and is barely used for the treatment of aspergillosis. The main route of 5FC activation in A. fumigatus comprises its deamination into 5-fluorouracil (5FU) by FcyA, which is followed by Uprt-mediated 5FU phosphoribosylation into 5-fluorouridine monophosphate (5FUMP). In this study, we characterized and examined the role of a metabolic bypass that generates this nucleotide via 5-fluorouridine (5FUR) through uridine phosphorylase and uridine kinase activities. Resistance profiling of mutants lacking distinct pyrimidine salvage activities suggested a minor contribution of the alternative route in 5FUMP formation. We further analyzed the contribution of drug efflux in 5FC tolerance and found that A. fumigatus cells exposed to 5FC reduce intracellular fluoropyrimidine levels through their export into the environment. This release, which was particularly high in mutants lacking Uprt, generates a toxic environment for cytosine deaminase lacking mutants as well as mammalian cells. Employing the broad-spectrum fungal efflux pump inhibitor clorgyline, we demonstrate synergistic properties of this compound in combination with 5FC, 5FU as well as 5FUR.
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Watkins, William J., Rémy C. Lemoine, Lee Chong, Aesop Cho, Thomas E. Renau, Bonnie Kuo, Vickie Wong, et al. "Quinazolinone fungal efflux pump inhibitors. Part 2: In vitro structure–activity relationships of (N-methyl-piperazinyl)-containing derivatives." Bioorganic & Medicinal Chemistry Letters 14, no. 20 (October 2004): 5133–37. http://dx.doi.org/10.1016/j.bmcl.2004.07.071.
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Dekkerová, Jaroslava, Lucia Černáková, Samuel Kendra, Elisa Borghi, Emerenziana Ottaviano, Birgit Willinger, and Helena Bujdáková. "Farnesol Boosts the Antifungal Effect of Fluconazole and Modulates Resistance in Candida auris through Regulation of the CDR1 and ERG11 Genes." Journal of Fungi 8, no. 8 (July 27, 2022): 783. http://dx.doi.org/10.3390/jof8080783.
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Candida auris is considered a serious fungal pathogen frequently exhibiting a high resistance to a wide range of antifungals. In this study, a combination of the quorum-sensing molecule farnesol (FAR) and fluconazole (FLU) was tested on FLU-resistant C. auris isolates (C. auris S and C. auris R) compared to the susceptible C. auris H261. The aim was to assess the possible synergy between FAR and FLU, by reducing the FLU minimal inhibitory concentration, and to determine the mechanism underlying the conjunct effect. The results confirmed a synergic effect between FAR and FLU with a calculated FIC index of 0.75 and 0.4 for C. auris S and C. auris R, respectively. FAR modulates genes involved in azole resistance. When FAR was added to the cells in combination with FLU, a significant decrease in the expression of the CDR1 gene was observed in the resistant C. auris isolates. FAR seems to block the Cdr1 efflux pump triggering a restoration of the intracellular content of FLU. These results were supported by observed increasing accumulation of rhodamine 6G by C. auris cells. Moreover, C. auris treated with FAR showed an ERG11 gene down-regulation. Overall, these results suggest that FAR is an effective modulator of the Cdr1 efflux pump in C. auris and, in combination with FLU, enhances the activity of this azole, which might be a promising strategy to control infections caused by azole-resistant C. auris.