Identification of small molecules that selectively inhibit fluconazole-resistant Candida albicans in the presence of fluconazole but not in its absence

The effectiveness of the potent Antifungal drug fluconazole has been compromised by the rise of drug-resistant Fungal pathogens. It has been observed that inhibition of heat shock protein 90 (HSP90) can reverse drug resistance in Candida; however, it is challenging to find fungal-specific inhibitors of HSP90 that do not also impair the human host protein. The Molecular Libraries Probe Production Centers Network (MLPCN) library was screened in duplicate dosings to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no Antifungal activity when administered as a single agent. A piperazinyl quinoline (CID 1251584) was identified as the initial hit, and after considerable SAR studies, was selected as the new probe compound (CID 1251584/ML189).