Wednesday, September 27, 2023
9/27/2023
PROJECT SUMMARY Candida auris is an emerging pan-multidrug-resistant fungal pathogen and presents a serious global health threat. Importantly, C. auris is the first fungal pathogen showing pronounced and sometimes untreatable clinical drug resistance to all known antifungal classes, including echinocandins azoles, and amphotericin B. However, the diagnostic tools for the early detection of drug resistance in C. auris infections are either inadequate or not sensitive enough for the identification of drug resistant clinical isolates. Thus, the combination of antifungal drug resistance, along with a lack of sensitive diagnostic assays impair efficient therapeutic strategies to overcome or prevent drug resistance in C. auris. Hence, the overall objective is to develop and validate SuperSelective PCR assays for the detection of mutations in genes encoding echinocandin or azole resistance, despite an abundant background of wild-type C. auris DNA. We hypothesize that SuperSelective PCR assays will detect mutant C. auris with a sensitivity exceeding 1:104 mutant:wild type for single nucleotide polymorphisms at genetic loci conferring echinocandin or azole resistance. The premise is based on our proof-of-concept work with an C. auris FKS1 mutation conferring high-level echinocandin resistance. We expect to test our hypothesis and to accomplish the objectives by pursuing two Specific Aims: 1) Develop and validate a novel SuperSelective PCR platform to detect mutations in C. auris genes conferring resistance to echinocandin and azole antifungal drugs. 2) Validate SuperSelective PCR assays to detect echinocandin and azole heteroresistance in the kidney homogenates of mice with active candidiasis. The payoffs of this proposal are expected to be significant, because the proposed study will develop a novel SuperSelective primer PCR platform to identify mutations, heteroresistant or tolerant clinical C. auris isolates. It will also provide a framework for mechanistic understanding of multidrug resistance in C. auris.
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