Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses

Candida auris is a newly identified species causing invasive candidemia and candidiasis. It has broad multidrug resistance (MDR) not observed for other pathogenicCandida species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity againstCandida albicans and is an attractive candidate for treating MDR fungi, since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility ofC. auris to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority ofC. auris clinical isolates, including fluconazole-resistant strains, were highly sensitive to Hst 5: 55 to 90% of cells were killed by use of 7.5 μM Hst 5. Hst 5 was translocated to the cytosol and vacuole inC. auris cells; such translocation is required for the killing ofC. albicans by Hst 5. 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 thanC. albicans , and higher survival within neutrophils, which correlated with resistance to oxidative stressin vitro . Thus, resistance to reactive oxygen species (ROS) is likely one, though not the only, important factor in the killing ofC. auris by neutrophils. Hst 5 has broad and potent candidacidal activity, enabling it to combat MDRC. auris strains effectively.