The role of aneuploidy in the emergence of echinocandin resistance in human fungal pathogen Candida albicans

Abstract

Fungal diseases largely affect human and animal health and dramatically diminish food crop yields [1].Among fungi, systemic Candida infections are the second or third most common pathogens isolated from blood cultures in the USA [2].Candida albicans is still the predominant Candida species, causing up to 50% of candidemia despite an increase in diversity of Candida species isolated from clinical samples [3].In healthy individuals, C. albicans is a harmless inhabitant of mucosal surfaces throughout the body.However, in immune-compromised individuals, C. albicans can become a dangerous pathogen, causing severe or even fatal infections.In this review, we summarize recent data linking the reduced susceptibility of C. albicans cells to mainline echinocandin (ECN) drugs to aneuploidies of chromosomes 5 (Ch5) and Ch2. Evolution of ECN resistance and mechanisms influencing susceptibilityThe ECN drugs caspofungin, anidulafungin, and micafungin that are recommended as frontline therapy for candidiasis have few adverse actions and drug-drug interactions [4].ECN drugs kill C. albicans cells by inhibiting glucan synthase, thus interfering with biosynthesis of the cell wall.Unlike well-studied multiple resistance mechanisms to fluconazole, another common anticandidal from the azole class, there is only one generally recognized mechanism of clinical resistance to drugs from the ECN class.This mechanism involves point mutations in the essential FKS1 gene (orf19.2929)encoding a catalytic subunit of the 1,3-β-glucan synthase complex.Mutations are clustered in two "hotspot" regions, HS1 and HS2, encompassing residues from 641 to 649, and from 1,345 to 1,365, respectively [5].Mutations in these regions cause dramatic elevation of C. albicans minimum inhibitory concentration (MIC) values to ECNs and reduce the sensitivity of the glucan synthase to up to 3,000-fold, the concentration of caspofungin inhibiting 50% of enzymatic activity (IC50) [6].However, it has now become obvious that C. albicans possesses mechanisms independent of FKS1 mutations that can decrease susceptibility to ECNs, although these "alternative" mechanisms do not confer clinical resistance.These "alternative" mechanisms have been brought to light by dozens of clinical isolates of Candida species that display a wide range of increased MIC values for ECNs, including some at or below the MIC breakpoints, but, importantly, without canonical FKS1 mutations [7-10].Consistent with these observations, several laboratories found that mutants lacking FKS1 mutations, but displaying (albeit relatively modest) 2 to 8 fold increases of MIC, can be easily generated in vitro on agar plates supplemented with caspofungin.While FKS1 mutations leading to resistance can also arise in vitro, these are typically rare [11][12][13].Furthermore, while Cowen and colleagues observed evolution of ECN

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