Chemogenomic profiling of the fungal pathogen Candida albicans [PublishAheadOfPrint]

There are currently a small number of classes of antifungal drugs, and these drugs are known to target a very limited set of cellular functions. We derived a set of approximately 900 non-essential, transactivator-defective disruption strains from the tetracycline regulated GRACE strain collection of the fungal pathogen Candida albicans. This strain set was screened against classic antifungal drugs to identify gene inactivations that conferred either enhanced sensitivity or increased resistance to the compounds. We examined two azoles, fluconazole and posaconazole; two echinochandins, caspofungin and anidulafungin; as well as the polyene amphotericin B. Overall, the chemogenomic profiles within drug classes were highly similar, but there was little overlap between classes, suggesting the different drug classes were interacting with discrete networks of genes in C. albicans. We also tested two pyridine amides, designated GPI-LY7 and GPI-C107; these drugs gave very similar profiles that were distinct from the echinochandins, azoles or polyenes, supporting the idea they target a distinct cellular function. Intriguingly, where these gene sets can be compared to genetic disruptions conferring drug sensitivity in other fungi, we find very little correspondence in genes. Thus even though the drug targets are the same in the different species, the specific genetic profiles that can lead to drug sensitivity are distinct. This implies that chemogenomic screens in one organism may be poorly predictive of the profiles found in other organisms, and that drug sensitivity and resistance profiles can differ significantly among organisms even when the apparent target of the drug is the same.

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