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

Abstract

is a newly identified species causing invasive candidemia and candidiasis. It has broad multidrug resistance (MDR) not observed for other pathogenic species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against and is an attractive candidate for treating MDR fungi, since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of 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 in cells; such translocation is required for the killing of by Hst 5. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole. showed higher tolerance to oxidative stress than, and higher survival within neutrophils, which correlated with resistance to oxidative stress Thus, resistance to reactive oxygen species (ROS) is likely one, though not the only, important factor in the killing of by neutrophils. Hst 5 has broad and potent candidacidal activity, enabling it to combat MDR strains effectively.

Abrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida auris

“…The three clinical isolates of C. auris from the South Asian clade with fluconazole MIC greatly exceeding the tentative breakpoint of Ն32 mg/liter (AR0388, AR0389, and AR0390; fluconazole MIC, Ն256 mg/liter) were then selected for evaluation of CDR1, CDR2, MDR1, and MDR2 expression relative to the fluconazole-susceptible C. auris isolate of the South Asian clade AR0387 (B8441). Isolate AR0382, which is also of the South Asian clade, was not included because it exhibits an intermediary fluconazole MIC of 16 mg/ liter and a strong aggregative phenotype not observed among the other South Asian isolates in this collection (12). Additionally, because both fluconazole-susceptible and fluconazole-resistant isolates (applying the tentative FDA breakpoints) from the South American, African, and East Asian clades were not available from the AR Bank panel, isolates from these clades were not included.…”

Candida albicans Ras1 Inactivation Increases Resistance to Phagosomal Killing by Human Neutrophils

“…Intracellular survival assay of C. albicans strains within neutrophils. Survival assays were performed following the protocol described previously (54). Briefly, fungal and phagocytic cells were incubated in RPMI 1640 medium for 3 h at 37°C and 5% CO 2 at an MOI of 0.1.…”

Hog1 Regulates Stress Tolerance and Virulence in the Emerging Fungal Pathogen Candida auris

“…Such SAPKs are essential for fungal survival against host-imposed stresses and are key virulence determinants in human-, plant-, and insect-infecting fungal pathogens ( 18 – 20 ). However, with the exception of a recent study ( 21 ) revealing that C. auris is relatively resistant to reactive oxygen species, little else is known regarding the ability of this pathogen to sense and respond to physiologically relevant stresses. Here, we compared the stress resistance profile of C. auris with those of other Candida species and explored the role of the conserved Hog1 SAPK in stress signaling and virulence in this important emerging pathogen.…”