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Candida albicans Strains Adapted to Caspofungin Due to Aneuploidy Become Highly Tolerant under Continued Drug
Farha Husain1, Anshuman Yadav1, Sudisht K Sah1
1Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Abstract:
Candida albicans is a prevalent fungal pathogen of humans. Understanding the development of decreased susceptibility to ECN drugs of this microbe is of substantial interest, as it is viewed as an intermediate step allowing the formation of FKS1 resistance mutations. We used six previously characterized mutants that decreased caspofungin susceptibility either by acquiring aneuploidy of chromosome 5 (Ch5) or by aneuploidy-independent mechanisms. When we exposed these caspofungin-adapted mutants to caspofungin again, we obtained 60 evolved mutants with further decreases in caspofungin susceptibility, as determined with CLSI method. We show that the initial adaptation to caspofungin is coupled with the adaptation to other ECNs, such as micafungin and anidulafungin, in mutants with no ploidy change, but not in aneuploid mutants, which become more susceptible to micafungin and anidulafungin. Furthermore, we find that the initial mechanism of caspofungin adaptation determines the pattern of further adaptation as parentals with no ploidy change further adapt to all ECNs by relatively small decreases in susceptibility, whereas aneuploid parentals adapt to all ECNs, primarily by large decrease in susceptibilities. Our data suggest that either distinct or common mechanisms can govern adaptation to different ECNs.
Insights
Candida albicans adaptation to echinocandin drugs varies. Aneuploidy influences cross-resistance, suggesting distinct mechanisms for antifungal drug adaptation.
Area of Science:
- Mycology
- Antimicrobial Resistance
- Fungal Pathogenesis
Background:
- Candida albicans is a common human fungal pathogen.
- Understanding decreased susceptibility to echinocandin (ECN) drugs is crucial for combating resistance.
- Decreased susceptibility can be an intermediate step towards developing FKS1 resistance mutations.
Purpose of the Study:
- To investigate the mechanisms of further decreased susceptibility to ECN drugs in Candida albicans.
- To determine how initial adaptation to caspofungin influences adaptation to other ECNs (micafungin, anidulafungin).
- To explore the role of aneuploidy in ECN drug adaptation.
Main Methods:
- Utilized six previously characterized Candida albicans mutants with decreased caspofungin susceptibility (aneuploidy of chromosome 5 or aneuploidy-independent).
- Exposed these adapted mutants to caspofungin to generate 60 evolved mutants with further decreased susceptibility.
- Assessed susceptibility using the Clinical and Laboratory Standards Institute (CLSI) method.
Main Results:
- Initial caspofungin adaptation is coupled with adaptation to micafungin and anidulafungin in non-aneuploid mutants.
- Aneuploid mutants showed increased susceptibility to micafungin and anidulafungin after initial caspofungin adaptation.
- The initial adaptation mechanism dictates further adaptation patterns: non-aneuploid mutants show small susceptibility decreases, while aneuploid mutants exhibit large decreases across ECNs.
Conclusions:
- The mechanism of initial caspofungin adaptation influences subsequent adaptation to other echinocandins.
- Aneuploidy plays a significant role in determining cross-resistance patterns among echinocandin drugs.
- Distinct or common mechanisms may govern adaptation to different echinocandin drugs in Candida albicans.
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