Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species

Author:

Basso Virginia1,Garcia Angie1,Tran Dat Q.12,Schaal Justin B.1ORCID,Tran Patti1,Ngole Diana1,Aqeel Younus1,Tongaonkar Prasad1,Ouellette André J.13,Selsted Michael E.13ORCID

Affiliation:

1. Department of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

2. Oryn Therapeutics, Vacaville, California, USA

3. Norris Comprehensive Cancer Center of the University of Southern California, Los Angeles, California, USA

Abstract

ABSTRACT Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug-resistant (MDR) Candida species. Thus, there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of θ-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug-resistant clinical isolates of Candida albicans and non- albicans Candida species. Rhesus θ-defensin 1 (RTD-1), the prototype θ-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR C. albicans strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed C. albicans much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to Candida proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural θ-defensins isoforms against drug-resistant C. albicans isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR Candida auris. These results point to the potential of macrocyclic θ-defensins as structural templates for the design of antifungal therapeutics.

Funder

Oryn Therapeutics, LLC

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute of Dental and Craniofacial Research

Southern California Clinical and Translational Science Institute

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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