Persephacin Is a Broad-Spectrum Antifungal Aureobasidin Metabolite That Overcomes Intrinsic Resistance in Aspergillus fumigatus

Abstract

Fungi pose a persistent threat to humankind with worrying indications that emerging and re-emerging pathogens (e.g., Candida auris, Coccidioides spp., drug-resistant Aspergilli, and more) exhibit resistance to the limited number of approved antifungals. To address this problem, our team is exploring endophytic fungi as a resource for the discovery of new antifungal natural products. The rationale behind this decision is based on evidence that endophytes engage with plants in mutualistic relationships wherein some fungi actively participate by producing chemical defense measures that suppress pathogenic microorganisms. To improve the odds of bioactive metabolite discovery, we developed a new hands-free laser-cutting system capable of generating >50 plant samples per minute that, in turn, enabled our team to prepare and screen large numbers of endophytic fungi. One of the fungal isolates obtained in this way was identified as an Elsinoësp. that produced a unique aureobasidin analogue, persephacin (1). Some distinctive features of 1 are the absence of both phenylalanine residues combined with the incorporation of a novel amino acid residue, persephanine (9). Compound 1 exhibits potent antifungal effects against a large number of pathogenic yeast (including several clinical C. auris strains), as well as phylogenetically diverse filamentous fungi (e.g., Aspergillus f umigatus). In an ex vivo eye infection model, compound 1 outperformed standard-of-care treatments demonstrating the ability to suppress fluconazole-resistant Candida albicans and A. f umigatus at a concentration (0.1% solution) well below the clinically recommended levels used for fluconazole and natamycin (2% and 5% solutions, respectively). In 3D tissue models for acute dermal and ocular safety, 1 was found to be nontoxic and nonirritating at concentrations required to elicit antifungal activity. Natural product 1 appears to be a promising candidate for further investigation as a broad-spectrum antifungal capable of controlling a range of pathogens that negatively impact human, animal, and plant health.

Current Perspectives of Antifungal Therapy: A Special Focus on Candida auris

“…In another study, Persephacin, isolated from the endophytic fungus Sphaceloma sp., showed activity against a diverse range of fungal species ( C. albicans , C. glabrata , C. parapsilosis , C. krusei , C. kefyr , C. tropicalis, and C. auris ). Persephacin resulted in MIC values around 2.5 µg/mL, which was similar to the activity expressed by AmB [ 65 ]. A group of new linear lipopeptides (Myropeptin C–E and Myropeptin A1), isolated from the saprotrophic filamentous fungus Myrothecium inundatum , showed good inhibition of C. auris cells.…”

Current Perspectives of Antifungal Therapy: A Special Focus on <em>Candida auris</em>

“…In another study, Persephacin isolated from the endophytic fungus Sphaceloma sp showed activity against a wide spectrum of fungal species (C. albicans, C. glabrata, C. parapsilosis, C. krusei, C. kefyr, C. tropicalis and C. auris). Persephacin resulted in the MIC values around 2.5 µg/mL, which was equal to the activity expressed by Amp B [64]. A group of new linear lipopeptides (Myropeptin C−E and Myropeptin A1) isolated from saprotrophic filamentous fungus Myrothecium inundatum, also produced good inhibition in C. auris cells.…”

On the way to potential antifungal compounds: synthesis and in vitro activity of 2-benzofuranylacetic acid amides

“…In this context, remarkable progress is being made in the development of new bioactive compounds against phytopathogens such as FOX on a weekly basis. [10][11][12][13][14][15][16][17][18] However, many of these advancements come with a signicant drawback. Most active compounds are derived from natural sources, resulting in limited quantities that make it challenging to conduct thorough testing and eld evaluations.…”