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bioRxiv · 10.1101/2024.12.28.630619

Construction of a drug sensitised Candida auris strain

Hassan, M.·Furner-Pardoe, J.·Chen, Y.·Mason, A. J.·Rahman, K. M.·Sutton, J. M.·Hind, C.·Panaretou, B.
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Abstract

Candida auris is an emerging pathogenic fungus causing outbreaks of invasive disease in healthcare facilities worldwide with the majority of clinical isolates demonstrating intrinsic resistance to multiple drug classes. Therefore, there is a pressing need for new antifungals, but screening in wild-type C. auris strains may miss scaffolds which would be good subjects for med-chem projects as antifungals. Work presented here indicates that deletion of CDR1 and MDR1 in C. auris, respectively encoding an ATP-binding Cassette and a Major Facilitator Superfamily efflux pump, generates a strain that is hypersensitised to drugs and can act as a platform for antifungal drug screening. The cdr1{Delta}mdr1{Delta} mutant was 64- and 8- times more sensitive to fluconazole and voriconazole, respectively, compared with the wild-type strain. In a pilot study using a 2,000 compound library, use of the cdr1{Delta}mdr1{Delta} mutant identified over twice as many compounds compared to wild-type. When assessing the capacity to form biofilms, there was a modest difference in biomass between the wild-type and cdr1{Delta}mdr1{Delta} mutant, but there was little to no statistically significant difference observed when using a colorimetric dye that measured metabolic activity. Little to no statistically significant difference was observed between wild-type and the efflux pump mutant in virulence, as judged by the larval Galleria mellonella infectivity assay. Accordingly, the cdr1{Delta}mdr1{Delta} mutant will be useful when screening for drugs that limit formation of biofilms or limit fungal virulence, as these two properties are unaffected when drug efflux is compromised.

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Hassan, M., Furner-Pardoe, J., Chen, Y., Mason, A. J., Rahman, K. M., Sutton, J. M., Hind, C., Panaretou, B.. 2024-12-28. Construction of a drug sensitised Candida auris strain. https://doi.org/10.1101/2024.12.28.630619

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