Abstract
Fatty acids have known antifungal effects and are used in over-the-counter topical treatments. Screening of a collection of gene knockouts in Candida albicans revealed that one strain, carrying a deletion of the transcription factor DAL81, is very susceptible to the medium-chain fatty acid undecanoic acid. However, reintroducing DAL81 does not restore resistance, and editing DAL81 in a different background does not introduce sensitivity. Whole-genome sequencing revealed that the C. albicansdal81Δ/Δ strain has an extra copy of chromosomes 5 and 7. Reversion to resistance to undecanoic acid was induced by growing the sensitive strain in yeast extract-peptone-dextrose with 60 μg/ml undecanoic acid for up to 9 days. Nine isolates that regained some resistance to undecanoic acid lost one copy of chromosome 7. The copy number of chromosome 5 does not appear to affect resistance to fatty acids. Moreover, the sensitivity may be related to having two copies of haplotype B of chromosome 7. In addition, we find that C. albicans strain SN152, used to delete DAL81 and many other genes, has undergone a major loss of heterozygosity event on chromosome 2 and a smaller one on chromosome 3.IMPORTANCE Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeast Candida albicans and are associated with adaptation to stress and to antifungal drugs. Aneuploidy and LOH can also be induced during laboratory manipulations, such as during genetic transformation. We find that C. albicans strain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. One deletion strain generated in this background has acquired extra copies of chromosomes 5 and 7. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids.
Highlights
Fatty acids have known antifungal effects and are used in over-thecounter topical treatments
undec-10-enoic acid (UDA), an mediumchain fatty acids (MCFAs) with a single unsaturated bond, is used as a topical antifungal treatment for tinea pedis, a foot infection caused by dermatophyte fungi [20], and has been shown to inhibit growth of C. albicans in liquid culture and in biofilms [17, 18, 21, 22]
Arbour et al [29] observed that each of the eight chromosomes of C. albicans can become duplicated in strains from different genetic backgrounds, such as CAI-4, RM1000, BWP17, or SN95, following a variety of treatments, including fluconazole treatment, Ura-blaster-mediated gene deletion, insertion of a PCR-amplified cassette, and MPAR flipping
Summary
Fatty acids have known antifungal effects and are used in over-thecounter topical treatments. The copy number of chromosome 5 does not appear to affect resistance to fatty acids. IMPORTANCE Aneuploidy (changes in chromosome number) and loss of heterozygosity (LOH) occur frequently in the human-pathogenic yeast Candida albicans and are associated with adaptation to stress and to antifungal drugs. We find that C. albicans strain SN152, commonly used to generate gene deletions, has undergone a major LOH event on chromosome 2. We find that trisomy (three copies) of chromosome 7 is associated with sensitivity to fatty acids. Trisomy of chromosome R confers resistance to azoles, including fluconazole, ketoconazole, and miconazole [8]. This phenotype can be reversed when the extra copy of chromosome R is lost by serially passaging on drug-free medium
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