Mechanisms of Antifungal Drug Resistance

Cowen, Leah E.; Sanglard, Dominique; Howard, Susan J.; Rogers, P. David; Perlin, David S.

doi:10.1101/cshperspect.a019752

Cited by 493 publications

(455 citation statements)

References 216 publications

(230 reference statements)

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“…The emergence of azole-resistant Candida strains is an increasingly troubling clinical problem (33). One potential approach to addressing this problem is to identify adjuvants that modulate FLU susceptibility (34).…”

Section: Resultsmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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gOnly one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 g/ml. AR-12 is also active against azole-and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole-and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.T he treatment of life-threatening invasive fungal infections (IFIs) remains a significant challenge to modern medicine (1, 2). Two primary factors contribute to the difficult nature of IFI therapy. First, most IFIs affect people with compromised immune function, and therefore, IFI patients are more reliant on the efficacy of the antifungal drug than immunocompetent patients. Second, the development of effective antifungal drugs is difficult, because many fundamental biological processes are highly conserved between fungi and humans (3). Consequently, identifying molecules that kill the pathogen and spare the host is very challenging. Currently, only three primary classes of antifungal drugs are in clinical use: (i) azole ergosterol biosynthesis inhibitors (e.g., fluconazole [FLU]), (ii) polyene ergosterol binding agents (e.g., amphotericin B), and (iii) echinocandin 1,3-␤-D-glucan synthase inhibitors (e.g., caspofungin). The number of antifungal drugs pales in comparison to the number of distinct classes of antimicrobial agents, and, in fact, there are currently more classes of antiretroviral agents available for the treatment of HIV/AIDS than classes of antifungal drugs (2).The pace of antifungal drug development has been extremely slow. For example, the most recent addition to the antifungal pharmacopeia, the echinocandins, was discovered in the early 1970s and introduced into clinical practice in the early 2000s (3). Furthermore, no new drugs for the treatment of cryptococcal meningitis, one of the most important causes of infectious disease-related deaths in HIV/AIDS patients (4), have been introduced into clinical practice in more than 20 years. In fact, the current gold standard therapy is based on drugs (amphotericin B an...

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Section: Resultsmentioning

confidence: 99%

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Koselny

Green

DiDone

et al. 2016

Antimicrob Agents Chemother

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“…To date, more than 30 different Cyp51A point mutations conferring azole resistance have been described in clinical isolates and laboratory-derived mutants (11)(12)(13)(14). Moreover, some studies have indicated that there are many unexplored non-cyp51A mutations that contribute to azole resistance in A. fumigatus (15,16).…”

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confidence: 99%

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Wei

Chen

Gao

et al. 2017

Antimicrob Agents Chemother

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The rapid and global emergence of azole resistance in the human pathogen Aspergillus fumigatus has drawn attention. Thus, a thorough understanding of its mechanisms of drug resistance requires extensive exploration. In this study, we found that the loss of the putative calcium-dependent protein-encoding gene algA causes an increased frequency of azole-resistant A. fumigatus isolates. In contrast to previously identified azole-resistant isolates related to cyp51A mutations, only one isolate carries a point mutation in cyp51A (F219L mutation) among 105 independent stable azole-resistant isolates. Through next-generation sequencing (NGS), we successfully identified a new mutation (R243Q substitution) conferring azole resistance in the putative A. fumigatus farnesyltransferase Cox10 (AfCox10) (AFUB_065450). High-performance liquid chromatography (HPLC) analysis verified that the decreased absorption of itraconazole in related Afcox10 mutants is the primary reason for itraconazole resistance. Moreover, a complementation experiment by reengineering the mutation in a parental wild-type background strain demonstrated that both the F219L and R243Q mutations contribute to itraconazole resistance in an algAindependent manner. These data collectively suggest that the loss of algA results in an increased frequency of azole-resistant isolates with a non-cyp51A mutation. Our findings indicate that there are many unexplored non-cyp51A mutations conferring azole resistance in A. fumigatus and that algA defects make it possible to isolate drug-resistant alleles. In addition, our study suggests that genome-wide sequencing combined with alignment comparison analysis is an efficient approach to identify the contribution of single nucleotide polymorphism (SNP) diversity to drug resistance.KEYWORDS Aspergillus fumigatus, azole resistance, cox10, cyp51A, mutation T he filamentous fungus Aspergillus fumigatus, one of the major opportunistic fungal pathogens, causes invasive fungal infections (IFIs) among immunosuppressed patients, with a high mortality rate (1, 2). Currently, azole compounds are the primary clinical therapy drug for IFIs and have been widely used in agriculture as well (3, 4). However, with the emergence of azole-resistant isolates, the efficacy of azole antifungals has been restricted so that azole resistance is becoming a growing public health menace (5-8). Therefore, the identification of genes whose mutations lead to drug resistance can provide a complete understanding of the molecular mechanisms underlying azole resistance.Previous studies verified that the most common mechanisms of resistance to azole antifungals observed in A. fumigatus samples are due to Cyp51A mutations, which

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“…Multiple efforts have been evaluated to use biomarkers or patients risk factors to direct early empirical antifungal therapy (2,(28)(29)(30). However, it is increasingly clear that the selection of a correct antifungal treatment depends on AST due to the emergence of resistance (31)(32)(33). The available AST methods need at least 24 h to obtain confident results for therapy initiation (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Quick Detection of FKS1 Mutations Responsible for Clinical Echinocandin Resistance in Candida albicans

et al. 2015

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A rapid molecular-based assay for the detection of the Candida albicans FKS1 gene mutations responsible for resistance to echinocandin drugs was designed and evaluated. The assay consisted of a multiplexed PCR set of 5 tubes able to detect the most commonly described resistance mechanism, including FKS1 hot spot 1 and hot spot 2 mutations. The performance and specificity of the assay was evaluated using a double-blinded panel of 50 C. albicans strains. The assay showed a sensitivity of 96% and was able to detect all homozygous mutants included in the collection of strains, demonstrating that it is a robust, quick, and laborsaving method that is suitable for a routine clinical diagnostic laboratory.

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Mechanisms of Antifungal Drug Resistance

Cited by 493 publications

References 216 publications

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis

Screening and Characterization of a Non- cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance

Quick Detection of FKS1 Mutations Responsible for Clinical Echinocandin Resistance in Candida albicans

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