Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in Candida albicans

Abstract

Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy.

Aneuploidy Underlies Tolerance and Cross-Tolerance to Drugs in Candida parapsilosis

“…Resistance to TUN in S. cerevisiae is often conferred by specific aneuploid chromosomes ( 38 ); four of five TUN-resistant mutants were aneuploid, each having a different whole-chromosome aneuploidy pattern involving at least two chromosomes ( 38 ). Recently, we found that adaptation to TUN also emerges via aneuploidy in C. albicans ; 93.5% (58 out of 62) adaptors in this study carried Chr2 trisomy, and only 5 of these had another aneuploidy in addition to Chr2 trisomy ( 44 ). Thus, aneuploidy appears to be a common adaptive genome change that can confer tolerance or resistance to tunicamycin.…”

“…In addition to trisomy of Chr6, other aneuploidies (e.g., Chr3R/8Lx3+Chr5x3) also confer cross-tolerance, indicating that both TUN and AbA selection can appear with acquisition of a single aneuploidy. This resembles the situation in C. albicans , where Chr2 trisomy confers cross-adaptation to both caspofungin, an antifungal drug, and to hydroxyurea, an inhibitor of ribonucleotide reductase used in cancer chemotherapies ( 17 ), as well as to TUN ( 44 ). Where it has been tested, different genes on the same chromosome confer adaptation to the different drugs ( 17 , 27 , 54 ).…”

“…Where it has been tested, different genes on the same chromosome confer adaptation to the different drugs ( 17 , 27 , 54 ). However, some genes may influence responses to two of the drugs; for example, in C. albicans , MKK2 is required for tolerance to both TUN and caspofungin, but not for tolerance to hydroxyurea ( 44 ).…”

“…The broth microdilution assay was performed as described previously ( 44 ). For each strain, approximately 2.5 × 10 3 cells/ml were grown in 150 μl YPD broth with or without the drugs in a 96-well plate at 37°C.…”

Acquisition of cross-azole tolerance and aneuploidy inCandida albicansstrains evolved to posaconazole

“…Resistance has been attributed to increased gene dosage of drug transporters or their transcriptional activators (CDR1, CDR2, CZR1, and MRR1 on chr3 (Sanglard et al 1995(Sanglard et al , 1997Chau et al 2004;Coste et al 2004Coste et al , 2006Todd and Selmecki 2020), TAC1 on chr5 (Selmecki et al 2008)), stress response proteins (PBS2 on chr3 (Todd and Selmecki 2020); CGR1 on chr4 (Todd and Selmecki 2020)), and the target enzyme (ERG11 on chr5 (Chau et al 2004;Selmecki et al 2008)). Furthermore, since many genes are affected by an aneuploidy, non-targeted effects may be more common than with singlegene mutations; for example, chr2 aneuploidy selected under caspofungin exposure confers enhanced survival by different mechanisms to hydroxyurea (Yang et al 2019) and tunicamycin (Yang et al 2021b). In some cases, this may provide an enhanced selective effect for aneuploidy to sweep through a population.…”