Resistance to echinocandin-class antifungal drugs
David Perlin2007, Drug Resistance Updates
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Abstract
Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.
Related papers
Effect of Candida glabrata FKS1 and FKS2 Mutations on Echinocandin Sensitivity and Kinetics of 1,3- -D-Glucan Synthase: Implication for the Existing Susceptibility Breakpoint
Antimicrobial Agents and Chemotherapy, 2009
Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3--D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (V max ) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3--D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 g/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 g/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of >2 g/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
Correlating Echinocandin MIC and Kinetic Inhibition of fks1 Mutant Glucan Synthases for Candida albicans: Implications for Interpretive Breakpoints
Antimicrobial Agents and Chemotherapy, 2009
A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3--D-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K i increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N-and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K m values, although some mutations decreased the V max . Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3--D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >2 g/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <50-fold for the K i was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >0.5 g/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >2 g/ml for the three echinocandin drugs. The 1,3--D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<0.5 g/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
Positions and numbers of FKS mutations in Candida albicans selectively influence in vitro and in vivo susceptibilities to echinocandin treatment
Antimicrobial agents and chemotherapy, 2014
Candidemia is the fourth most common kind of microbial bloodstream infection, with Candida albicans being the most common causative species. Echinocandins are employed as the first-line treatment for invasive candidiasis until the fungal species is determined and confirmed by clinical diagnosis. Echinocandins block the FKS glucan synthases responsible for embedding β-(1,3)-d-glucan in the cell wall. The increasing use of these drugs has led to the emergence of antifungal resistance, and elevated MICs have been associated with single-residue substitutions in specific hot spot regions of FKS1 and FKS2. Here, we show for the first time the caspofungin-mediated in vivo selection of a double mutation within one allele of the FKS1 hot spot 1 in a clinical isolate. We created a set of isogenic mutants and used a hematogenous murine model to evaluate the in vivo outcomes of echinocandin treatment. Heterozygous and homozygous double mutations significantly enhance the in vivo resistance of C...
Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata
PLoS Pathogens, 2012
The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential.
Acquired Echinocandin Resistance in a Candida krusei Isolate Due to Modification of Glucan Synthase
Antimicrobial Agents and Chemotherapy, 2007
A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080K, in FKS1. The resulting Phe6553Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.
<i>FKS</i> Mutations and Elevated Echinocandin MIC Values among <i>Candida glabrata</i> Isolates from U.S. Population-Based Surveillance
Antimicrobial Agents and Chemotherapy, 2010
Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of >0.25 g/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n ؍ 2) or FKS2 (n ؍ 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations.
Assessing Resistance to the Echinocandin Antifungal Drug Caspofungin in Candida albicans by Profiling Mutations in FKS1
Antimicrobial Agents and Chemotherapy, 2006
Resistance of clinical isolates of Candida albicans to the echinocandin drug caspofungin is slowly emerging and is linked to mutations in short conserved regions in the FKS1 gene. The most prominent changes occurred at the serine 645 position in Fks1p with substitutions of proline, tyrosine, and phenylalanine. An allele-specific real-time PCR molecular-beacon assay was developed for rapid identification of drug resistance by targeting FKS1 mutations. Mutations altering serine 645 were reliably identified in both heterozygous and homozygous states. The molecular-beacon assay was used to evaluate two large collections of spontaneous mutants from separate strains of C. albicans with resistance (MICs, >16 g/ml) to caspofungin with the goal of understanding the relationship between FKS1 mutations and echinocandin resistance. Of 85 resistant isolates recovered, all were identified with mutations in FKS1; 93% showed changes at Ser645, with 62% displaying a characteristic S645P substitution expressed as either a homozygous or a heterozygous mutation in FKS1. Two other prominent amino acid substitutions, S645Y and S645F, were found at frequencies of 22% and 8%, respectively. Three new mutations were also identified: T1922C, G1932T, and C1934G, encoding F641S, L644F, and S645C substitutions, respectively. One strain had the double amino acid substitution L644F and S645C. Allele-specific probes were combined in a multiplex assay for reliable screening of known FKS1 mutations. These data support the importance of FKS1p substitutions in echinocandin resistance and demonstrate the feasibility of applying molecular screening for routine resistance assessment.
Molecular Characterization and In Vitro Antifungal Susceptibility of Candida Glabrata Clinical Isolates with Reduced Echinocandin Susceptibility and High Level Multi-Azole Resistance
Clinical microbiology, 2014
Candida glabrata is the second most commonly isolated yeast recovered from blood cultures in the United States. We characterized 85 C. glabrata clinical isolates recovered from various clinical specimens obtained from immunocompromised individuals. This collection was unique because it included a series of isolates recovered from the blood of a patient who only partially responded to antifungal therapy. In vitro activity of caspofungin, micafungin, anidulafungin, fluconazole, voriconazole and amphotericin B was evaluated. Most of the isolates were susceptible to the echinocandins, triazoles and amphotericin B. The geometric mean MIC of the antifungals for the susceptible isolates (n=79) were as follows: caspofungin, 0.061315 ± 0.076934; micafungin, 0.123521 ± 0.457202; anidulafungin, 0.044158 ± 0.895249; fluconazole, 7.013461 ± 20.56794; voriconazole, 0.324939 ± 1.051247; amphotericin B, 0.474923 ± 0.162994. Five of the six serial blood isolates showed a reduced echinocandin susceptibility (RES) to the echinocandins and the triazoles. Characterization of the hot spot 1 region of FKS1, FKS2 and FKS3 showed no amino acid alterations. However, the genes coding for the drug efflux proteins CgCDR1, CgCDR2, CgSNQ2, as well as Cgcyp51 were over-expressed in the isolates with RES and azole resistance compared to the susceptible isolates, indicating that the upregulation of the synthesis of efflux proteins and the drug target is responsible for conferring resistance to triazoles in these isolates. These results demonstrate that multiechinocandin and multi-azole resistant C. glabrata clinical isolates can emerge under the selection pressure imposed by specific drug therapy over a relatively short period of time.
FKS2 Mutations Associated with Decreased Echinocandin Susceptibility of Candida glabrata following Anidulafungin Therapy
Antimicrobial Agents and Chemotherapy, 2011
This is the first case report of Candida glabrata-disseminated candidiasis describing the acquisition of echinocandin resistance following anidulafungin treatment. The initial isolates recovered were susceptible to echinocandins. However, during 27 days of anidulafungin treatment, two resistant strains were isolated (from the blood and peritoneal fluid). The resistant peritoneal fluid isolate exhibited a Ser663Pro mutation in position 1987 of FKS2 HS1 (hot spot 1), whereas the resistant blood isolate displayed a phenylalanine deletion (Phe659).
Antifungal Drug Resistance: Mechanisms, Epidemiology, and Consequences for Treatment
Antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. In vitro susceptibility testing is often used to select agents with likely activity for a given infection, but perhaps its most important use is in identifying agents that will not work, i.e., to detect resistance. Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe. Data gathered by these standardized tests are useful (in conjunction with other forms of data) for calculating clinical breakpoints and epidemiologic cutoff values (ECVs). Clinical breakpoints should be selected to optimize detection of non-wild-type (WT) strains of pathogens, and they should be species-specific and not divide WT distributions of important target species. ECVs are the most sensitive means of identifying strains with acquired resistance mechanisms. Various mechanisms can lead to acquired resistance of Candida species to azole drugs, the most common being induction of the efflux pumps encoded by the MDR or CDR genes, and acquisition of point mutations in the gene encoding for the target enzyme (ERG11). Acquired resistance of Candida species to echinocandins is typically mediated via acquisition of point mutations in the FKS genes encoding the major subunit of its target enzyme. Antifungal resistance is associated with elevated minimum inhibitory concentrations, poorer clinical outcomes, and breakthrough infections during antifungal treatment and prophylaxis. Candidemia due to Candida glabrata is becoming increasingly common, and C glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents. This situation requires continuing attention. Rates of azole-resistant Aspergillus fumigatus are currently low, but there are reports of emerging resistance, including multi-azole resistant isolates in parts of Europe.
Related papers
Effect of Candida glabrata FKS1 and FKS2 Mutations on Echinocandin Sensitivity and Kinetics of 1,3-β- d -Glucan Synthase: Implication for the Existing Susceptibility Breakpoint
Antimicrobial Agents and Chemotherapy, 2009
Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata . A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-β- d -glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme ( V max ) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-β- d -glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or mica...
Quick detection of FKS1 Mutations Responsible for Clinical Echinocandin Resistance in Candida albicans
Journal of Clinical Microbiology, 2015
Novel FKS mutations associated with echinocandin resistance in Candida species
Antimicrobial agents …, 2010
We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3--D-glucan synthase inhibition assay.
Coping with stress and the emergence of multidrug resistance in fungi
PLoS pathogens, 2015
FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance
Antimicrobial Agents and Chemotherapy, 2010
Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 ( n = 2) or FKS2 ( n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2 . The predominant mutation was mutation of FKS2 -encoded serine 663 to proline (S663P), found in 10 of...
Target enzyme mutations confer differential echinocandin susceptibilities in Candida kefyr
Antimicrobial agents and chemotherapy, 2014
Candida kefyr is an increasingly reported pathogen in patients with hematologic malignancies. We studied a series of bloodstream isolates that exhibited reduced echinocandin susceptibilities (RES). Clinical and surveillance isolates were tested for susceptibilities to all three echinocandins, and those isolates displaying RES to one or more echinocandins were selected for molecular and biochemical studies. The isolates were analyzed for genetic similarities, and a subset was analyzed for mutations in the echinocandin target gene FKS1 and glucan synthase echinocandin sensitivities using biochemical methods. The molecular typing did not indicate strong genetic relatedness among the isolates except for a series of strains recovered from a single patient. Two unrelated isolates with RES had previously uncharacterized FKS1 mutations: R647G and deletion of amino acid 641 (F641Δ). Biochemical analysis of the semipurified R647G glucan synthase generated differential echinocandin sensitivity...
Benzylic Dehydroxylation of Echinocandin Antifungal Drugs Restores Efficacy against Resistance Conferred by Mutated Glucan Synthase
Journal of the American Chemical Society, 2022
Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in FKS genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3S,4S-dihydroxy-L-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-resistant Candida strains. The dehydroxylated compounds did not significantly affect the viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistant Candida strains, which contain mutations in the FKS1 and/or FKS2 genes of the parental strains, identified amino acids of the Fks proteins that are likely to reside in proximity to the L-homotyrosine residue of the bound drug. This study describes the first example of a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal of antifungal drugs, against resistant fungal pathogens.
A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility
Antimicrobial Agents and Chemotherapy, 2008
Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4-to 18.8-fold-reduced V max values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
Susceptibility of fluconazole-resistant clinical isolates of Candida spp. to echinocandin LY303366, itraconazole and amphotericin B
Journal of …, 2000
Specific Substitutions in the Echinocandin Target Fks1p Account for Reduced Susceptibility of Rare Laboratory and Clinical Candida sp. Isolates
Antimicrobial Agents and Chemotherapy, 2005
An association between reduced susceptibility to echinocandins and changes in the 1,3--D-glucan synthase (GS) subunit Fks1p was investigated. Specific mutations in fks1 genes from Saccharomyces cerevisiae and Candida albicans mutants are described that are necessary and sufficient for reduced susceptibility to the echinocandin drug caspofungin. One group of amino acid changes in ScFks1p, ScFks2p, and CaFks1p defines a conserved region (Phe 641 to Asp 648 of CaFks1p) in the Fks1 family of proteins. The relationship between several of these fks1 mutations and the phenotype of reduced caspofungin susceptibility was confirmed using site-directed mutagenesis or integrative transformation. Glucan synthase activity from these mutants was less susceptible to caspofungin inhibition, and heterozygous and homozygous Cafks1 C. albicans mutants could be distinguished based on the shape of inhibition curves. The C. albicans mutants were less susceptible to caspofungin than wild-type strains in a murine model of disseminated candidiasis. Five Candida isolates with reduced susceptibility to caspofungin were recovered from three patients enrolled in a clinical trial. Four C. albicans strains showed amino acid changes at Ser 645 of CaFks1p, while a single Candida krusei isolate had a deduced R1361G substitution. The clinical C. albicans mutants were less susceptible to caspofungin in the disseminated candidiasis model, and GS inhibition profiles and DNA sequence analyses were consistent with a homozygous fks1 mutation. Our results indicate that substitutions in the Fks1p subunit of GS are sufficient to confer reduced susceptibility to echinocandins in S. cerevisiae and the pathogens C. albicans and C. krusei.
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