Competitive Fitness of Fluconazole-Resistant Clinical Candida albicans Strains

Abstract

The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1 and Tac1, which result in constitutive overexpression of multidrug efflux pumps, and Upc2, which result in constitutive overexpression of ergosterol biosynthesis genes. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug. To investigate whether fluconazole-resistant clinical C. albicans isolates have overcome the fitness costs of drug resistance, we assessed the relative fitness of C. albicans isolates containing resistance mutations in these transcription factors in competition with matched drug-susceptible isolates from the same patients. Most of the fluconazole-resistant isolates were outcompeted by the corresponding drug-susceptible isolates when grown in rich medium without fluconazole. On the other hand, some resistant isolates with gain-of-function mutations in MRR1 did not exhibit reduced fitness under these conditions. In a mouse model of disseminated candidiasis, three out of four tested fluconazole-resistant clinical isolates did not exhibit a significant fitness defect. However, all four fluconazole-resistant isolates were outcompeted by the matched susceptible isolates in a mouse model of gastrointestinal colonization, demonstrating that the effects of drug resistance on in vivo fitness depend on the host niche. Collectively, our results indicate that the fitness costs of drug resistance in C. albicans are not easily remediated, especially when proper control of gene expression is required for successful adaptation to life within a mammalian host.

A 23 bp cyp51A Promoter Deletion Associated With Voriconazole Resistance in Clinical and Environmental Isolates of Neocosmospora keratoplastica

“…The ∼6,500-fold increased CYP51A mRNA expression levels suggest that, like in A. fumigatus (Abastabar et al, 2019) and the plant fungal pathogen F. graminearum (Liu et al, 2011;Fan et al, 2013), CYP51A of N. keratoplastica is also a key player in the observed azole resistance phenotype of FSSC species. Sterol biosynthesis of Saccharomycotina species like S. cerevisiae or C. albicans is regulated by the sterol regulatory zinccluster TF Upc2 (Yang et al, 2015;Popp et al, 2017). Sterol biosynthesis of many other eukaryotes, including fungal species like A. fumigatus, C. neoformans and Schizosaccharomyces pombe, and also mammals including Homo sapiens, is regulated by a different type of sterol regulator: a TF called SREBP.…”

A Hyperactive Form of the Zinc Cluster Transcription Factor Stb5 Causes YOR1 Overexpression and Beauvericin Resistance in Candida albicans

“…We therefore tested the effect of a hyperactive Stb5 on the fluconazole sensitivity of two matched pairs of fluconazole-susceptible and fluconazole-resistant clinical C. albicans isolates in the absence and presence of beauvericin. Both resistant isolates contain GOF mutations in Tac1 (G980E in Gu5 and N977D in DSY296) that result in CDR1/CDR2 overexpression (10,17,24,25). As shown in Fig.…”

“…Upc2 regulates the expression of ergosterol biosynthesis genes, whereas Tac1 and Mrr1 control the expression of the multidrug efflux pumps encoded by CDR1/CDR2 and MDR1, respectively (5)(6)(7)(8). Gain-of-function (GOF) mutations in these transcription factors result in the constitutive overexpression of their target genes and are a common cause of fluconazole resistance in clinical C. albicans isolates (5,7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

A Nanoemulsion as an Effective Treatment Against Human Pathogenic Fungi

“…The ability of C. albicans to form biofilms, which increases antifungal drug resistance, is a major virulence factor observed in the clinical setting (12, 13). To test the efficacy of NB-201 on C. albicans biofilms, two multi-drug resistant clinical isolates TW1 and TW17 (21) were chosen. The C. albicans clinical isolates TW1 and TW17 were plated on 96-well plates and allowed to form a biofilm over the course of 24 hours (PFB).…”