Chromosome 1 trisomy confers resistance to aureobasidin A in Candida albicans

Lijun Zheng; Yi Xu; Yubo Dong; Xiaowen Ma; Chen Wang; Feng Yang; Liangsheng Guo

doi:10.3389/fmicb.2023.1128160

Chromosome 1 trisomy confers resistance to aureobasidin A in Candida albicans

Front Microbiol. 2023 Mar 17:14:1128160. doi: 10.3389/fmicb.2023.1128160. eCollection 2023.

Authors

Lijun Zheng¹, Yi Xu², Yubo Dong², Xiaowen Ma², Chen Wang², Feng Yang³, Liangsheng Guo⁴

Affiliations

¹ Department of Ultrasound Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China.
² Department of Pharmacy, The 960 Hospital of PLA, Jinan, China.
³ Department of Pharmacology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Abstract

Introduction: Candida albicans is a prevalent opportunistic human fungal pathogen. However, there are currently very few antifungal treatments available. Inositol phosphoryl ceramide synthase is an essential and fungal-specific protein that also provides a novel and promising antifungal target. Aureobasidin A is a widely used inhibitor of inositol phosphoryl ceramide synthase, however the mechanism of resistance to aureobasidin A is largely unknown in pathogenic fungi.

Methods: Here we investigated how C. albicans adapted to low and high concentrations of aureobasidin A.

Results and discussions: We identified trisomy of chromosome 1 as the predominant mechanism of rapid adaptation. Resistance to aureobasidin A was unstable because of the inherent instability of aneuploids. Importantly, chromosome 1 trisomy simultaneously regulated genes which were associated with aureobasidin A resistance that are on this aneuploid chromosome as well as on other chromosomes. Furthermore, the pleiotropic effect of aneuploidy caused altered resistance not only to aureobasidin A but also to other antifungal drugs including caspofungin and 5-flucytosine. We posit aneuploidy provides a rapid and reversible mechanism of development of drug resistance and cross resistance in C. albicans.

Keywords: Candida albicans; aneuploidy; antifungal drugs; aureobasidin A; sphingolipid biosynthesis.

Grants and funding

This study was supported by the Science and Technology Development Plan of Suzhou (SLJ2022018), Scientific Research Project of Suzhou Commission of Health (GSWS2020028) to LG, and the National Natural Science Foundation of China (81402978) to YX.