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Published on: December 28, 2017
Multiple Genes of Candida albicans Influencing Echinocandin Susceptibility in Caspofungin-Adapted Mutants
Sudisht K Sah1, Soumyaroop Bhattacharya2,3, Anshuman Yadav1
1Department of Biochemistry and Biophysics, University of Rochester Medical Centergrid.412750.5, Rochester, New York, USA.
Abstract:
Candida albicans is an opportunistic human fungal pathogen that causes invasive infections in immunocompromised individuals. Despite the high anticandidal activity among the echinocandins (ECNs), a first-line therapy, resistance remains an issue. Furthermore, many clinical isolates display decreased ECN susceptibility, a physiological state which is thought to lead to resistance. Determining the factors that can decrease susceptibility is of high importance. We searched for such factors genome-wide by comparing the transcriptional profiles of five mutants that acquired decreased caspofungin susceptibility in vitro in the absence of canonical FKS1 resistance mutations. The mutants were derived from two genetic backgrounds and arose due to independent mutational events, some with monosomic chromosome 5 (Ch5). We found that the mutants exhibit common transcriptional changes. In particular, all mutants upregulate five genes from Ch2 in concert. Knockout experiments show that all five genes positively influence caspofungin and anidulafungin susceptibility and play a role in regulating the cell wall mannan and glucan contents. The functions of three of these genes, orf19.1766, orf19.6867, and orf19.5833, were previously unknown, and our work expands the known functions of LEU42 and PR26. Importantly, orf19.1766 and LEU42 have no human orthologues. Our results provide important clues as to basic mechanisms of survival in the presence of ECNs while identifying new genes controlling ECN susceptibility and revealing new targets for the development of novel antifungal drugs.
Insights
New research identifies five genes in Candida albicans that increase susceptibility to echinocandins (ECNs), a crucial antifungal drug class. These findings reveal novel targets for combating drug resistance in invasive fungal infections.
Area of Science:
- Mycology
- Antimicrobial Resistance
- Fungal Pathogenesis
Background:
- Candida albicans is an opportunistic pathogen causing invasive infections in immunocompromised individuals.
- Echinocandins (ECNs) are first-line antifungals, but resistance and decreased susceptibility are significant clinical challenges.
- Understanding factors contributing to decreased ECN susceptibility is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To identify novel genetic factors that contribute to decreased echinocandin (ECN) susceptibility in Candida albicans.
- To investigate the genome-wide transcriptional changes associated with acquired ECN resistance.
- To explore potential new drug targets for overcoming ECN resistance.
Main Methods:
- Comparative transcriptional profiling of five Candida albicans mutants with decreased caspofungin susceptibility.
- Analysis of mutants derived from different genetic backgrounds and mutational events, including some with monosomic chromosome 5.
- Gene knockout experiments to validate the role of identified genes in ECN susceptibility and cell wall composition.
Main Results:
- Common transcriptional changes were observed across all mutants, notably the coordinated upregulation of five genes on chromosome 2.
- Knockout of these five genes significantly increased susceptibility to caspofungin and anidulafungin.
- These genes regulate cell wall mannan and glucan content, with three having previously unknown functions (orf19.1766, orf19.6867, orf19.5833).
- orf19.1766 and LEU42 lack human orthologues, suggesting potential for targeted antifungal therapies.
Conclusions:
- The identified five genes are key regulators of ECN susceptibility in Candida albicans.
- These genes represent novel targets for developing new antifungal drugs to combat resistance.
- Understanding these survival mechanisms provides insights into fungal adaptation to echinocandin stress.
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