Abstract
The increasing resistance of fungi to antibiotics is a severe challenge in public health, and newly effective drugs are required. Promising potential medications are lipopeptides, linear antimicrobial peptides (AMPs) conjugated to a lipid tail, usually at the N-terminus. In this paper, we investigated the in vitro and in vivo antifungal activity of three short myristoylated and non-myristoylated peptides derived from a mutant of the AMP Chionodracine. We determined their interaction with anionic and zwitterionic membrane-mimicking vesicles and their structure during this interaction. We then investigated their cytotoxic and hemolytic activity against mammalian cells. Lipidated peptides showed a broad spectrum of activity against a relevant panel of pathogen fungi belonging to Candida spp., including the multidrug-resistant C. auris. The antifungal activity was also observed vs. biofilms of C. albicans, C. tropicalis, and C. auris. Finally, a pilot efficacy study was conducted on the in vivo model consisting of Galleria mellonella larvae. Treatment with the most-promising myristoylated peptide was effective in counteracting the infection from C. auris and C. albicans and the death of the larvae. Therefore, this myristoylated peptide is a potential candidate to develop antifungal agents against human fungal pathogens.
Highlights
In recent years, extensive abuse of chemicals to control diseases has been associated with the increasing number of multidrug-resistant pathogens
We investigated the in vitro and in vivo antifungal activity of three short myristoylated and nonmyristoylated peptides derived from a mutant of the antimicrobial peptides (AMPs) Chionodracine
We proved the antifungal activity against a relevant panel of pathogenic fungi belonging to Candida spp., and biofilms formed by C. albicans, C. tropicalis, and C. auris
Summary
Extensive abuse of chemicals to control diseases has been associated with the increasing number of multidrug-resistant pathogens. The growth of fungi and bacteria resistant to conventional antimicrobial agents represents one of the biggest concerns worldwide [1–4]. Systemic fungal infections are challenging and represent a significant cause of morbidity and mortality, especially for immune-compromised people. Fungi infect billions of people every year, with a high rate of mortality of about 1.5 million [1]. Pathogenic fungi, like human cells, are eukaryotic, and potential selective drugs can only attack limited targets. The only licensed antifungal therapies for humans, polyenes, azoles, echinocandins, and flucytosine, suffer several limitations due to cross-target toxicity. Antimicrobial peptides (AMPs), which are key components of the innate immune system [4], are ubiquitously present in vertebrates, invertebrates, plants, and bacteria and represent promising antifungal candidates. In 1948, Bacillomycin, the first AMP with antifungal activity, was isolated from the bacteria Bacillus subtilis [5] and, in recent years, others were evidenced [6,7]
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