The yeast Candida albicans can be an opportunistic pathogen and also develop resistance to antimycotic drugs. IMIB researchers Irene Hampe and Joachim Morschhäuser report in PLoS Pathogens that the fungus becomes resistant to both drug therapy and innate host defenses by a related mechanism to establish itself in the oral cavity.

Candida albicans is normally a harmless commensal in the oral cavity and the gastrointestinal and urogenital tracts of most healthy people. Nevertheless, this fungus can also cause symptomatic infections, especially when host defenses are weakened. Although such infections are usually effectively treated with antimycotic drugs, C. albicans can develop drug resistance, particularly after long-term therapy of oral candidiasis with azole antifungals. Azole resistance is often caused by activating mutations in zinc cluster transcription factors, a family of transcriptional regulators that is specific to the fungal kingdom. Such gain-of-function mutations result in the constitutive overexpression of their target genes, including genes encoding efflux pumps that remove the drugs from fungal cells.

Irene Hampe and Joachim Morschhäuser from IMIB, together with collaborators from Buffalo/USA, investigated if C. albicans can use a similar mechanism to acquire resistance against defense molecules produced by the human host itself. They took advantage of a comprehensive library of C. albicans strains containing artificially activated forms of all its zinc cluster transcription factors, which was previously generated in the Morschhäuser lab. Using this approach, they found that a hyperactive form of a transcription factor termed Mrr1 (multidrug resistance regulator 1) conferred increased resistance to the antimicrobial peptide histatin 5, which is produced in the saliva of humans to protect the oral cavity against pathogens and acts intracellularly to kill C. albicans. Intriguingly, C. albicans strains that have acquired resistance against the azole antifungal drug fluconazole often contain mutations in Mrr1 that activate the transcription factor. The research team showed that such strains not only have acquired fluconazole resistance but also increased resistance to histatin 5, which was partially caused by Mrr1-mediated overexpression of the multidrug efflux pump MDR1. This represents an additional advantage for the fungus in the oral cavity that may compensate for the fitness costs caused by the deregulated gene expression in the absence of the drug. These findings demonstrate that antimycotic therapy can promote the evolution of strains that have simultaneously acquired increased resistance against an innate host defense mechanism and are thereby better adapted to specific host niches.Reference:Hampe IAI, Friedman J, Edgerton M, Morschhäuser J (2017) An acquired mechanism of antifungal drug resistance simultaneously enables Candida albicans to escape from intrinsic host defenses. PLoS Pathog 13(9): e1006655. doi.org/10.1371/journal.ppat.1006655.

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