Does transcriptional heterogeneity facilitate the development of genetic drug resistance?

Farquhar, Kevin S.; Koohi, Samira Rasouli; Charlebois, Daniel A.

doi:10.1002/bies.202100043

Cited by 10 publications

(10 citation statements)

References 67 publications

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“…The tolerance to fungistatic and fungicidal drugs observed in some of the clinical C. auris isolates in our study appears to be a reversible phenomenon, as previously described for clinical C. albicans isolates [ 56 ]. The tolerant cells growing inside ZOI upon subculture are indistinguishable from the parental population, suggesting the presence of phenotypic heterogeneity instead of genetic variation.…”

Section: Discussionsupporting

confidence: 82%

Identification and Elimination of Antifungal Tolerance in Candida auris

et al. 2023

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Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogen C. auris is of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure in C. auris has been recently attributed to antifungal “tolerance”. Tolerance is a phenomenon whereby a slow-growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays, together with image analysis, to investigate antifungal tolerance in C. auris to all three classes of antifungal drugs used to treat invasive candidiasis. We find that (1) C. auris is tolerant to several common fungistatic and fungicidal drugs, which in some cases can be detected after 24 h, as well as after 48 h, of antifungal drug exposure; (2) the tolerant phenotype reverts to the susceptible phenotype in C. auris; and (3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine in some cases reduces or eliminates tolerance and resistance in patient-derived C. auris isolates. These results suggest that tolerance contributes to treatment failure in C. auris infections for a broad range of antifungal drugs, and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.

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Section: Discussionsupporting

confidence: 82%

Identification and Elimination of Antifungal Tolerance in Candida auris

et al. 2023

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“…The tolerance to fungistatic and fungicidal drugs observed in the clinical C. auris isolates our study appears to be a reversible phenomenon, as previously described for clinical C. albicans isolates [57]. The tolerant cells growing inside ZOI upon sub-culture are indistinguishable from parental population suggesting the presence of phenotypic heterogeneity instead of genetic variations.…”

Section: Discussionsupporting

confidence: 81%

Identification and Elimination of Antifungal Tolerance inCandida auris

Koohi

Shankarnarayan

Galon

et al. 2022

Preprint

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Antimicrobial resistance is a global health crisis to which pathogenic fungi make a substantial contribution. The human fungal pathogenC. aurisis of particular concern due to its rapid spread across the world and its evolution of multidrug resistance. Fluconazole failure inC. aurishas been recently attributed to antifungal ``tolerance''. Tolerance is a phenomenon whereby a slow growing subpopulation of tolerant cells, which are genetically identical to susceptible cells, emerges during drug treatment. We use microbroth dilution and disk diffusion assays together with image analysis to investigate antifungal tolerance inC. auristo all three classes of antifungal drugs used to treat invasive candidiasis. We find that 1)C. aurisis tolerant to several common fungistatic and fungicidal drugs, which in some cases can be visually detected after 24 hours, as well as after 48 hours, of antifungal drug exposure; 2) the tolerant phenotype reverts to the susceptible phenotype inC. auris; and 3) combining azole, polyene, and echinocandin antifungal drugs with the adjuvant chloroquine reduces or eliminates tolerance and resistance in patient-derivedC. aurisisolates. These results suggest that tolerance contributes to treatment failure inC. aurisinfections for a broad range of antifungal drugs and that antifungal adjuvants may improve treatment outcomes for patients infected with antifungal-tolerant or antifungal-resistant fungal pathogens.

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“…It has been considered that the development of drug resistance is the evolutionary dynamic of a population transforming from gene expression "noise", epigenetic mechanisms, and gene mutation mechanisms-a process that tends towards genetic stability [22,50]. Notably, overexpression of the drug efflux pump gene cdr4 was necessary for evolutionary adaptation to the azole stress in N. crassa as significantly increased transcript levels of cdr4 were detected in all four evolved resistant strains.…”

Section: Discussionmentioning

confidence: 99%

Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress

Zhou

Yin

et al. 2022

JoF

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Multidrug resistance, defined as the resistance to multiple drugs in different categories, has been an increasing serious problem. Limited antifungal drugs and the rapid emergence of antifungal resistance prompt a thorough understanding of how the occurrence of multidrug resistance develops and which mechanisms are involved. In this study, experimental evolution was performed under single-azole-drug stress with the model filamentous fungus Neurospora crassa. By about 30 weeks of continuous growth on agar plates containing ketoconazole or voriconazole with weekly transfer, four evolved multidrug-resistant strains 30thK1, 30thK2, 26thV1, and 24thV2 were obtained. Compared to the ancestral strain, all four strains increased resistance not only to commonly used azoles, including ketoconazole, voriconazole, itraconazole, fluconazole, and triadimefon, but also to antifungal drugs in other categories, including terbinafine (allylamine), amorolfine (morpholine), amphotericin B (polyene), polyoxin B (chitin synthesis inhibitor), and carbendazim (β-tubulin inhibitor). After 8 weeks of growth on agar plates without antifungal drugs with weekly transfer, these evolved strains still displayed multidrug-resistant phenotype, suggesting the multidrug resistance could be stably inherited. Transcriptional measurement of drug target genes and drug transporter genes and deletion analysis of the efflux pump gene cdr4 in the evolved strains suggest that overexpression of cdr4 played a major role in the resistance mechanisms for azoles and terbinafine in the evolved strains, particularly for 30thK2 and 26thV1, and evolved drug-resistant strains had less intracellular ketoconazole accumulation and less disruption of ergosterol accumulations under ketoconazole stress compared to wild type. Mutations specifically present in evolved drug-resistant strains were identified by genome re-sequencing, and drug susceptibility test of knockout mutants for most of mutated genes suggests that mutations in 16 genes, functionally novel in drug resistance, potentially contribute to multidrug resistance in evolved strains.

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Does transcriptional heterogeneity facilitate the development of genetic drug resistance?

Cited by 10 publications

References 67 publications

Identification and Elimination of Antifungal Tolerance in Candida auris

Identification and Elimination of Antifungal Tolerance in Candida auris

Identification and Elimination of Antifungal Tolerance inCandida auris

Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress

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