scholarly journals Loss of Mitochondrial Functions Associated with Azole Resistance in Candida glabrata Results in Enhanced Virulence in Mice

2011 ◽  
Vol 55 (5) ◽  
pp. 1852-1860 ◽  
Author(s):  
Sélène Ferrari ◽  
Maurizio Sanguinetti ◽  
Flavia De Bernardis ◽  
Riccardo Torelli ◽  
Brunella Posteraro ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Abc Transporter ◽  
Candida Glabrata ◽  
Selective Advantage ◽  
Azole Resistance ◽  
Content Type ◽  
Mitochondrial Functions ◽  
Abc Transporter Genes

ABSTRACTMitochondrial dysfunction is one of the possible mechanisms by which azole resistance can occur inCandida glabrata. Cells with mitochondrial DNA deficiency (so-called “petite mutants”) upregulate ATP binding cassette (ABC) transporter genes and thus display increased resistance to azoles. Isolation of suchC. glabratamutants from patients receiving antifungal therapy or prophylaxis has been rarely reported. In this study, we characterized two sequential and relatedC. glabrataisolates recovered from the same patient undergoing azole therapy. The first isolate (BPY40) was azole susceptible (fluconazole MIC, 4 μg/ml), and the second (BPY41) was azole resistant (fluconazole MIC, >256 μg/ml). BPY41 exhibited mitochondrial dysfunction and upregulation of the ABC transporter genesC. glabrata CDR1(CgCDR1),CgCDR2, andCgSNQ2. We next assessed whether mitochondrial dysfunction conferred a selective advantage during host infection by testing the virulence of BPY40 and BPY41 in mice. Surprisingly, even within vitrogrowth deficiency compared to BPY40, BPY41 was more virulent (as judged by mortality and fungal tissue burden) than BPY40 in both systemic and vaginal murine infection models. The increased virulence of the petite mutant correlated with a drastic gain of fitness in mice compared to that of its parental isolate. To understand this unexpected feature, genome-wide changes in gene expression driven by the petite mutation were analyzed by use of microarrays duringin vitrogrowth. Enrichment of specific biological processes (oxido-reductive metabolism and the stress response) was observed in BPY41, all of which was consistent with mitochondrial dysfunction. Finally, some genes involved in cell wall remodelling were upregulated in BPY41 compared to BPY40, which may partially explain the enhanced virulence of BPY41. In conclusion, this study shows for the first time that mitochondrial dysfunction selectedin vivounder azole therapy, even if strongly affectingin vitrogrowth characteristics, can confer a selective advantage under host conditions, allowing theC. glabratamutant to be more virulent than wild-type isolates.

scholarly journals Reversal of Azole Resistance inCandida albicansby Sulfa Antibacterial Drugs

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Hassan E. Eldesouky ◽  
Abdelrahman Mayhoub ◽  
Tony R. Hazbun ◽  
Mohamed N. Seleem
Keyword(s):  
Treatment Options ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Azole Resistance ◽  
Global Public Health ◽  
Sulfa Drugs ◽  
Antibacterial Drugs ◽  
Content Type

ABSTRACTInvasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reversing azole resistance inCandida. In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity inCandida albicans. Surprisingly, the majority of assayed sulfa drugs (15 of 21) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with fractional inhibitory concentration index (ΣFIC) values ranging from <0.0312 to 0.25. Remarkably, five sulfa drugs were able to reverse azole resistance in a clinically achievable range. The structure-activity relationships (SARs) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibitCandidabiofilm by 40%in vitrowas confirmed. In addition, the effects of sulfa-fluconazole combinations onCandidagrowth kinetics and efflux machinery were explored. Finally, using aCaenorhabditis elegansinfection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activityin vivo, reducingCandidain infected worms by ∼50% compared to the control.

scholarly journals Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

2001 ◽  
Vol 45 (4) ◽  
pp. 1174-1183 ◽  
Author(s):  
Dominique Sanglard ◽  
Francoise Ischer ◽  
Jacques Bille
Keyword(s):  
Abc Transporter ◽  
High Frequency ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Atp Binding ◽  
Transporter Gene ◽  
Atp Binding Cassette

ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.

scholarly journals T-2307 Shows Efficacy in a Murine Model of Candida glabrata Infection despite In Vitro Trailing Growth Phenomena

2010 ◽  
Vol 54 (9) ◽  
pp. 3630-3634 ◽  
Author(s):  
Eio Yamada ◽  
Hiroshi Nishikawa ◽  
Nobuhiko Nomura ◽  
Junichi Mitsuyama
Keyword(s):  
Murine Model ◽  
Candida Glabrata ◽  
Viable Count ◽  
Control Group ◽  
Alamar Blue ◽  
Inhibition Of Growth ◽  
Mitochondrial Functions ◽  
Clinically Significant

ABSTRACT T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. In our preliminary studies, Candida glabrata exhibited significant trailing growth (partial inhibition of growth over an extended range of antifungal concentrations) in the presence of T-2307 when it was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines with 0.2% glucose and 48 h of incubation, making reading of the MIC difficult. In the present study, we attempted to attenuate trailing growth to avoid misreading of the MIC. On the basis of the hypothesis that T-2307 may inhibit the mitochondrial functions of cells, the carbon source or the glucose concentration in the medium was changed. The trailing growth of C. glabrata ATCC 90030 in the presence of T-2307 was attenuated as the concentration of glucose in the medium decreased to 0.1% or lower, and trailing growth was completely inhibited when glycerol was used. A susceptibility test using Alamar blue was performed to facilitate reading of the MIC without changing the composition of the medium and provided a clear MIC endpoint at 24 h. To investigate if T-2307 shows efficacy against trailing isolates in vivo, we evaluated the efficacy of T-2307 in a murine model of disseminated candidiasis caused by C. glabrata. T-2307 at 0.05 mg/kg of body weight/day significantly decreased the viable count in the kidneys compared to that for the control group (P < 0.05). It would be better to test the susceptibility of C. glabrata to T-2307 using modified media or Alamar blue to avoid misreading of the MIC due to the significant trailing growth.

scholarly journals Partial Complementation of Sinorhizobium meliloti bacA Mutant Phenotypes by the Mycobacterium tuberculosis BacA Protein

2012 ◽  
Vol 195 (2) ◽  
pp. 389-398 ◽  
Author(s):  
M. F. F. Arnold ◽  
A. F. Haag ◽  
S. Capewell ◽  
H. I. Boshoff ◽  
E. K. James ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Abc Transporter ◽  
Sinorhizobium Meliloti ◽  
Mammalian Host ◽  
Insertion Mutant ◽  
Atpase Domain ◽  
Content Type ◽  
Transporter Protein

ABSTRACTTheSinorhizobium melilotiBacA ABC transporter protein plays an important role in its nodulating symbiosis with the legume alfalfa (Medicago sativa). TheMycobacterium tuberculosisBacA homolog was found to be important for the maintenance of chronic murine infections, yet itsin vivofunction is unknown. In the legume plant as well as in the mammalian host, bacteria encounter host antimicrobial peptides (AMPs). We found that theM. tuberculosisBacA protein was able to partially complement the symbiotic defect of anS. melilotiBacA-deficient mutant on alfalfa plants and to protect this mutantin vitrofrom the antimicrobial activity of a synthetic legume peptide, NCR247, and a recombinant human β-defensin 2 (HBD2). This finding was also confirmed using anM. tuberculosisinsertion mutant. Furthermore,M. tuberculosisBacA-mediated protection of the legume symbiontS. melilotiagainst legume defensins as well as HBD2 is dependent on its attached ATPase domain. In addition, we show thatM. tuberculosisBacA mediates peptide uptake of the truncated bovine AMP, Bac71-16. This process required a functional ATPase domain. We therefore suggest thatM. tuberculosisBacA is important for the transport of peptides across the cytoplasmic membrane and is part of a complete ABC transporter. Hence, BacA-mediated protection against host AMPs might be important for the maintenance of latent infections.

scholarly journals Upregulation of the Adhesin Gene EPA1 Mediated by PDR1 in Candida glabrata Leads to Enhanced Host Colonization

mSphere ◽  
2016 ◽  
Vol 1 (2) ◽  
Author(s):  
Luis A. Vale-Silva ◽  
Beat Moeckli ◽  
Riccardo Torelli ◽  
Brunella Posteraro ◽  
Maurizio Sanguinetti ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Epithelial Cells ◽  
Candida Glabrata ◽  
Resistance Mechanism ◽  
Cell Types ◽  
Host Cells ◽  
Regulation Mechanism ◽  
Content Type

ABSTRACT Candida glabrata is an important fungal pathogen in human diseases and is also rapidly acquiring drug resistance. Drug resistance can be mediated by the transcriptional activator PDR1, and this results in the upregulation of multidrug transporters. Intriguingly, this resistance mechanism is associated in C. glabrata with increased virulence in animal models and also with increased adherence to specific host cell types. The C. glabrata adhesin gene EPA1 is a major contributor of virulence and adherence to host cells. Here, we show that EPA1 expression is controlled by PDR1 independently of subtelomeric silencing, a known EPA1 regulation mechanism. Thus, a relationship exists between PDR1, EPA1 expression, and adherence to host cells, which is critical for efficient virulence. Our results demonstrate that acquisition of drug resistance is beneficial for C. glabrata in fungus-host relationships. These findings further highlight the challenges of the therapeutic management of C. glabrata infections in human patients. Candida glabrata is the second most common Candida species causing disseminated infection, after C. albicans. C. glabrata is intrinsically less susceptible to the widely used azole antifungal drugs and quickly develops secondary resistance. Resistance typically relies on drug efflux with transporters regulated by the transcription factor Pdr1. Gain-of-function (GOF) mutations in PDR1 lead to a hyperactive state and thus efflux transporter upregulation. Our laboratory has characterized a collection of C. glabrata clinical isolates in which azole resistance was found to correlate with increased virulence in vivo. Contributing phenotypes were the evasion of adhesion and phagocytosis by macrophages and an increased adhesion to epithelial cells. These phenotypes were found to be dependent on PDR1 GOF mutation and/or C. glabrata strain background. In the search for the molecular effectors, we found that PDR1 hyperactivity leads to overexpression of specific cell wall adhesins of C. glabrata. Further study revealed that EPA1 regulation, in particular, explained the increase in adherence to epithelial cells. Deleting EPA1 eliminates the increase in adherence in an in vitro model of interaction with epithelial cells. In a murine model of urinary tract infection, PDR1 hyperactivity conferred increased ability to colonize the bladder and kidneys in an EPA1-dependent way. In conclusion, this study establishes a relationship between PDR1 and the regulation of cell wall adhesins, an important virulence attribute of C. glabrata. Furthermore, our data show that PDR1 hyperactivity mediates increased adherence to host epithelial tissues both in vitro and in vivo through upregulation of the adhesin gene EPA1. IMPORTANCE Candida glabrata is an important fungal pathogen in human diseases and is also rapidly acquiring drug resistance. Drug resistance can be mediated by the transcriptional activator PDR1, and this results in the upregulation of multidrug transporters. Intriguingly, this resistance mechanism is associated in C. glabrata with increased virulence in animal models and also with increased adherence to specific host cell types. The C. glabrata adhesin gene EPA1 is a major contributor of virulence and adherence to host cells. Here, we show that EPA1 expression is controlled by PDR1 independently of subtelomeric silencing, a known EPA1 regulation mechanism. Thus, a relationship exists between PDR1, EPA1 expression, and adherence to host cells, which is critical for efficient virulence. Our results demonstrate that acquisition of drug resistance is beneficial for C. glabrata in fungus-host relationships. These findings further highlight the challenges of the therapeutic management of C. glabrata infections in human patients.

scholarly journals Genes Involved in Galactooligosaccharide Metabolism in Lactobacillus reuteri and Their Ecological Role in the Gastrointestinal Tract

2019 ◽  
Vol 85 (22) ◽  
Author(s):  
Monchaya Rattanaprasert ◽  
Jan-Peter van Pijkeren ◽  
Amanda E. Ramer-Tait ◽  
Maria Quintero ◽  
Car Reen Kok ◽  
...  
Keyword(s):  
Type Strain ◽  
Wild Type Strain ◽  
Lactobacillus Reuteri ◽  
Selective Advantage ◽  
Wild Type ◽  
Carbohydrate Source ◽  
Content Type ◽  
Gnotobiotic Mice

ABSTRACT Strains of Lactobacillus reuteri are commonly used as probiotics due to their demonstrated therapeutic properties. Many strains of L. reuteri also utilize the prebiotic galactooligosaccharide (GOS), providing a basis for formulating synergistic synbiotics that could enhance growth or persistence of this organism in vivo. In this study, in-frame deletion mutants were constructed to characterize the molecular basis of GOS utilization in L. reuteri ATCC PTA-6475. Results suggested that GOS transport relies on a permease encoded by lacS, while a second unidentified protein may function as a galactoside transporter. Two β-galactosidases, encoded by lacA and lacLM, sequentially degrade GOS oligosaccharides and GOS disaccharides, respectively. Inactivation of lacL and lacM resulted in impaired growth in the presence of GOS and lactose. In vitro competition experiments between the wild-type and ΔlacS ΔlacM strains revealed that the GOS-utilizing genes conferred a selective advantage in media with GOS but not glucose. GOS also provided an advantage to the wild-type strain in experiments in gnotobiotic mice but only on a purified, no sucrose diet. Differences in cell numbers between GOS-fed mice and mice that did not receive GOS were small, suggesting that carbohydrates other than GOS were sufficient to support growth. On a complex diet, the ΔlacS ΔlacM strain was outcompeted by the wild-type strain in gnotobiotic mice, suggesting that lacL and lacM are involved in the utilization of alternative dietary carbohydrates. Indeed, the growth of the mutants was impaired in raffinose and stachyose, which are common in plants, demonstrating that α-galactosides may constitute alternate substrates of the GOS pathway. IMPORTANCE This study shows that lac genes in Lactobacillus reuteri encode hydrolases and transporters that are necessary for the metabolism of GOS, as well as α-galactoside substrates. Coculture experiments with the wild-type strain and a gos mutant clearly demonstrated that GOS utilization confers a growth advantage in medium containing GOS as the sole carbohydrate source. However, the wild-type strain also outcompeted the mutant in germfree mice, suggesting that GOS genes in L. reuteri also provide a basis for utilization of other carbohydrates, including α-galactosides, ordinarily present in the diets of humans and other animals. Collectively, our work provides information on the metabolism of L. reuteri in its natural niche in the gut and may provide a basis for the development of synbiotic strategies.

scholarly journals Comparative Effects of Micafungin, Caspofungin, and Anidulafungin against a Difficult-To-Treat Fungal Opportunistic Pathogen, Candida glabrata

2011 ◽  
Vol 56 (3) ◽  
pp. 1215-1222 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Fiorenza Orlando ◽  
Maurizio Sanguinetti ◽  
Brunella Posteraro ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Laboratory Strain ◽  
Opportunistic Pathogen ◽  
Content Type ◽  
Susceptible Isolate ◽  
Resistant Strains ◽  
Time Kill ◽  
Higher Doses

ABSTRACTThe aim of this study was to compare thein vitroandin vivoactivities of micafungin, caspofungin, and anidulafungin againstCandida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against aC. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains ofC. glabratawere selected:C. glabrata30, a laboratory strain harboring the mutation Fks2p-P667T, andC. glabrata51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs.In vivostudies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached.

scholarly journals Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

2014 ◽  
Vol 58 (12) ◽  
pp. 7390-7397 ◽  
Author(s):  
Maria Isabel Veiga ◽  
Nuno S. Osório ◽  
Pedro Eduardo Ferreira ◽  
Oscar Franzén ◽  
Sabina Dahlstrom ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Abc Transporter ◽  
Parasite Clearance ◽  
Antimalarial Drugs ◽  
Multidrug Resistance Protein ◽  
Content Type ◽  
Resistance Protein

ABSTRACTPlasmodium falciparumhas the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including theApicomplexaparasites.P. falciparumgenome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters:Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studiedPfmrp2. The role ofPfmrp2polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of thePfmrp2genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found thatPfmrp2harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identifiedPfmrp2polymorphisms with alteredin vitrosusceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggestedPfmrp2polymorphisms modulate the parasite'sin vitroresponse to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association within vivoparasite clearance. In conclusion, our study reveals that thePfmrp2gene is the most diverse ABC transporter known inP. falciparumwith a potential role in antimalarial drug resistance.

scholarly journals Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Andrew T. Nishimoto ◽  
Sarah G. Whaley ◽  
Nathan P. Wiederhold ◽  
Qing Zhang ◽  
Christopher M. Yates ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Invasive Infection ◽  
Content Type ◽  
Zinc Cluster ◽  
Transcription Factor Genes ◽  
Fluconazole Resistant

ABSTRACT VT-1161 and VT-1598 are promising investigational tetrazole antifungals that have shown in vitro and in vivo activity against Candida and other fungi. Candida glabrata is a problematic opportunistic pathogen that is associated with high mortality in invasive infection, as well as both intrinsic and rapidly acquired antifungal resistance. The MICs of VT-1161 and VT-1598 were determined by CLSI methodology to evaluate their in vitro activities against clinical C. glabrata isolates and strains containing individual deletions of the zinc cluster transcription factor genes PDR1 and UPC2A as well as the efflux transporter genes CDR1, PDH1, and SNQ2. Overall, both tetrazoles demonstrated relative activities comparable to those of the tested triazole antifungals against clinical C. glabrata isolates (MIC range, 0.25 to 2 mg/liter and 0.5 to 2 μg/ml for VT-1161 and VT-1598, respectively). Deletion of the PDR1 gene in fluconazole-resistant matched clinical isolate SM3 abolished the decreased susceptibility phenotype completely for both VT-1161 and VT-1598, similarly to the triazoles. UPC2A deletion also increased susceptibility to both triazoles and tetrazoles but to a lesser extent than PDR1 deletion. Of the three major transporter genes regulated by Pdr1, CDR1 deletion resulted in the largest MIC reductions for all agents tested, while PDH1 and SNQ2 deletion individually impacted MICs very little. Overall, both VT-1161 and VT-1598 have comparable activities to those of the available triazoles, and decreased susceptibility to these tetrazoles in C. glabrata is driven by many of the same known resistance mechanisms.

scholarly journals An Azole-Tolerant Endosomal Trafficking Mutant of Candida albicans Is Susceptible to Azole Treatment in a Mouse Model of Vaginal Candidiasis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Brian M. Peters ◽  
Arturo Luna-Tapia ◽  
Hélène Tournu ◽  
Jeffrey M. Rybak ◽  
P. David Rogers ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Vaginal Candidiasis ◽  
Azole Resistance ◽  
Endosomal Trafficking ◽  
Wild Type ◽  
Content Type ◽  
Azole Antifungals

ABSTRACT We recently reported that a Candida albicans endosomal trafficking mutant continues to grow after treatment with the azole antifungals. Herein, we report that the vps21Δ/Δ mutant does not have a survival advantage over wild-type isolates after fluconazole treatment in a mouse model of vaginal candidiasis. Furthermore, loss of VPS21 does not synergize with established mechanisms of azole resistance, such as overexpression of efflux pumps or of Erg11p, the target enzyme of the azoles. In summary, although loss of VPS21 function enhances C. albicans survival after azole treatment in vitro, it does not seem to affect azole susceptibility in vivo.

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