Fluconazole Resistant Candida auris is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses [PublishAheadOfPrint]

Candida auris is a newly identified species causing invasive candidemia and candidiasis, and has broad multidrug resistance (MDR) not observed for other pathogenic Candida species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against C. albicans, and is an attractive candidate to treat MDR fungi since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of C. auris to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of C. auris clinical isolates, including fluconazole resistant strains, were highly sensitive to Hst 5 with 55-90% of cells being killed using 7.5 μM Hst 5. Hst 5 was translocated to the cytosol and vacuole in C. auris cells, which are requirements for Hst 5 killing of C. albicans. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole. C. auris showed higher tolerance to oxidative stress compared to C. albicans, and higher survival within neutrophils which correlated with resistance to oxidative stress in vitro. Thus, ROS resistance is likely one, though not the only, important factor in neutrophil killing of C. auris. Hst 5 has a broad and potent candidacidal activity to effectively combat MDR C. auris strains.

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