Harnessing Random Peptide Mixtures to Overcome Multidrug-Resistant Fungal Infections

Invasive fungal infections, characterized by high mortality rates, present a growing health concern due to the limited spectrum of effective drugs, escalating numbers of immunocompromised patients, and the rapid emergence of drug resistance. Addressing this challenge requires alternative therapeutic strategies. Candidate drugs should fulfill key requirements to qualify for clinical use, including negligible host toxicity, high in vitro and in vivo antifungal activity, in vivo stability, and modes of actions that reduce the potential for the emergence of resistant strains. Antimicrobial peptides (AMPs) stand out as a promising class of compounds to combat antimicrobial resistance. Capitalizing on the unique characteristics of AMPs, we have developed a novel approach, to synthesize random peptide mixtures (RPMs) with robust bactericidal properties against drug-resistant bacteria. Here, we evaluate the antifungal potential of RPMs. Our findings demonstrate high potency of RPMs against Candida auris , a newly emerged multidrug-resistant human fungal pathogen. In vitro studies demonstrated the effective eradication of C. auris by FK20 RPMs, with scanning electron microscopy revealing substantial damage to the fungal outer membrane, while confocal microscopy confirms their ability to penetrate C. auris cells. Importantly, our study elucidates that FK20 RPMs effectively hinder the development of resistance in C. auris , as confirmed by experimental evolution assays. Moreover, a synergistic effect is observed when combining FK20 RPMs with the antifungal drug caspofungin, effectively inhibiting biofilm formation. Lastly, we demonstrate the significant therapeutic potential of FK20 RPM in a murine model of systemic candidiasis. Our findings underscore the promise of RPMs as novel, efficacious, and safe treatment for drug-resistant fungal infections.