Mechanisms of Drug Resistance in Candida albicans

Sanglard, Dominique

doi:10.1007/978-3-319-50409-4_15

Cited by 5 publications

(3 citation statements)

References 117 publications

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“…Finally, the general analysis of epistasis of resistant and tolerant mutations presented above is not limited to genetic tolerance and resistance, but also relevant for the interaction between resistant mutations and phenotypic tolerance, such as observed in biofilms (54), a major concern in recalcitrant infections. Moreover, the ability of cells to survive lethal treatments by tolerance and persistence has been shown to be relevant in the context of antifungals (55) as well as anticancer drugs (56). Therefore, we expect that the framework for the interaction between resistance, tolerance, and persistence mutations presented here to be widely applicable for the study of drug resistance evolution.…”

Section: Discussionmentioning

confidence: 99%

Epistasis between antibiotic tolerance, persistence, and resistance mutations

Levin-Reisman

Brauner

Ronin

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

151

135

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Understanding the evolution of microorganisms under antibiotic treatments is a burning issue. Typically, several resistance mutations can accumulate under antibiotic treatment, and the way in which resistance mutations interact, i.e., epistasis, has been extensively studied. We recently showed that the evolution of antibiotic resistance in Escherichia coli is facilitated by the early appearance of tolerance mutations. In contrast to resistance, which reduces the effectiveness of the drug concentration, tolerance increases resilience to antibiotic treatment duration in a nonspecific way, for example when bacteria transiently arrest their growth. Both result in increased survival under antibiotics, but the interaction between resistance and tolerance mutations has not been studied. Here, we extend our analysis to include the evolution of a different type of tolerance and a different antibiotic class and measure experimentally the epistasis between tolerance and resistance mutations. We derive the expected model for the effect of tolerance and resistance mutations on the dynamics of survival under antibiotic treatment. We find that the interaction between resistance and tolerance mutations is synergistic in strains evolved under intermittent antibiotic treatment. We extend our analysis to mutations that result in antibiotic persistence, i.e., to tolerance that is conferred only on a subpopulation of cells. We show that even when this population heterogeneity is included in our analysis, a synergistic interaction between antibiotic persistence and resistance mutations remains. We expect our general framework for the epistasis in killing conditions to be relevant for other systems as well, such as bacteria exposed to phages or cancer cells under treatment.

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Section: Discussionmentioning

confidence: 99%

Epistasis between antibiotic tolerance, persistence, and resistance mutations

Levin-Reisman

Brauner

Ronin

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

151

135

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“…The prevalence of antifungal resistance due to the prolonged use of fungistatic drugs has become a challenge in the treatment of fungal infections, highlighting the urgent need for developments in the antifungal pipeline 4 – 7 . Among the variety of molecular mechanisms of fungal resistance that Candida species have evolved 8 , 9 , the upregulation of the efflux pumps MDR1 and/or CDR1 / CDR2 contributes to azole resistance in most clinical Candida albicans isolates 10 , 11 . MDR1 and CDR1 / CDR2 expression are regulated by the transcription factors Mrr1 and Tac1, respectively.…”

Section: Introductionmentioning

confidence: 99%

Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation

et al. 2018

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Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here we present a method for identification of PEPSs, and show that conjugation with mitochondria-targeting triphenylphosphonium cation (TPP+) can enhance or restore the compounds’ antifungal activity. The screening method involves co-culturing a wild-type C. albicans strain and a Cdr efflux pump-deficient strain, labelled with different fluorescent proteins. We identify several PEPSs from a library of natural terpenes, and restore their antifungal activity against wild-type and azole-resistant C. albicans by conjugation with TPP+. The most active conjugate (IS-2-Pi-TPP) kills C. albicans cells, prevents biofilm formation and eliminates preformed biofilms, without inducing significant resistance. The antifungal activity is accompanied by mitochondrial dysfunction and increased levels of intracellular reactive oxygen species. In addition, IS-2-Pi-TPP is effective against C. albicans in a mouse model of skin infection.

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“…For example, amphotericin B, triazoles and echinocandins are commonly used for the treatment of candidiasis and get a good treatment [18]. However, the emerging resistance to antifungal drugs of C. albicans in human infections has become a major concern in recent years [19][20][21]. Above all, the antifungal drugs commonly used to treat fungal infections are limited and have considerable disadvantages; hence, novel and efficient antifungal strategy is badly needed.…”

Section: Introductionmentioning

confidence: 99%

Effects of nanosecond pulsed electric fields (nsPEFs) on the human fungal pathogenCandida albicans:anin vitrostudy

Guo

Dang

Wang

et al. 2018

J. Phys. D: Appl. Phys.

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Candida albicans is the leading human fungal pathogen that causes many life-threatening infections. Notably, the current clinical trial data indicate that Candida species shows the emerging resistance to anti-fungal drugs. The aim of this study was to evaluate the antifungal effects of nanosecond pulsed electric fields (nsPEFs) as a novel drug-free strategy in vitro. In this study, we investigated the inactivation and permeabilization effects of C. albicans under different nsPEFs exposure conditions (100 pulses, 100 ns in duration, intensities of 20, 40 kV cm −1 ). Cell death was studied by annexin-V and propidium iodide staining. The changes of intracellular Ca 2+ concentration after nsPEFs treatment were observed using Fluo-4 AM. Results show that C. albicans cells and biofilms were both obviously inhibited and destroyed after nsPEFs treatment. Furthermore, C. albicans cells were significantly permeabilized after nsPEFs treatment. Additionally, nsPEFs exposure led to a large amount of DNA and protein leakage. Importantly, nsPEFs induced a field strength-dependent apoptosis in C. albicans cells. Further experiments revealed that Ca 2+ involved in nsPEFs induced C. albicans apoptosis. In conclusion, this proof-of-concept study provides a potential alternative drug-free strategy for killing pathogenic Candida species.

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Mechanisms of Drug Resistance in Candida albicans

Cited by 5 publications

References 117 publications

Epistasis between antibiotic tolerance, persistence, and resistance mutations

Epistasis between antibiotic tolerance, persistence, and resistance mutations

Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation

Effects of nanosecond pulsed electric fields (nsPEFs) on the human fungal pathogenCandida albicans:anin vitrostudy

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