Dataset Information

Microbial Metabolite Inspired β-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

ABSTRACT: Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by penetrating the fungal cytoplasm, generating reactive oxygen, and inducing fungal apoptosis. The optimal PDAP displays potent antifungal activity with minimum inhibitory concentration as low as 0.4 µg mL^-1 against Candida albicans, negligible hemolysis and cytotoxicity, and no susceptibility to antifungal resistance. In addition, PDAP effectively inhibits the formation of fungal biofilms and eradicates the mature biofilms. In vivo studies show that PDAP is safe and effective in treating fungal keratitis, which suggests PDAPs as promising new antifungal agents.

SUBMITTER: Zhang D

PROVIDER: S-EPMC9108603 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Microbial Metabolite Inspired β-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Zhang Donghui D Shi Chao C Cong Zihao Z Chen Qi Q Bi Yufang Y Zhang Junyu J Ma Kaiqian K Liu Shiqi S Gu Jiawei J Chen Minzhang M Lu Ziyi Z Zhang Haodong H Xie Jiayang J Xiao Ximian X Liu Longqiang L Jiang Weinan W Shao Ning N Chen Sheng S Zhou Min M Shao Xiaoyan X Dai Yidong Y Li Maoquan M Zhang Lixin L Liu Runhui R

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220320 14

Potent and selective antifungal agents are urgently needed due to the quick increase of serious invasive fungal infections and the limited antifungal drugs available. Microbial metabolites have been a rich source of antimicrobial agents and have inspired the authors to design and obtain potent and selective antifungal agents, poly(DL-diaminopropionic acid) (PDAP) from the ring-opening polymerization of β-amino acid N-thiocarboxyanhydrides, by mimicking ε-poly-lysine. PDAP kills fungal cells by p ...[more]

PMID: 35307990

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Project description:Fungal infections in humans are difficult to treat, with very limited drug options. Due to a confluence of factors, there is an urgent need for innovation in the antifungal drug space, particularly to combat increasing antifungal drug resistance. Our previous studies showed that Cdc50, a subunit of fungal lipid translocase (flippase), is essential for Cryptococcus neoformans virulence and required for antifungal drug resistance, suggesting that fungal lipid flippase could be a novel drug target. Here, we characterized an antifungal peptide, Cryptomycinamide (KKOO-NH2), derived from a 9-amino acid segment of the C. neoformans Cdc50 protein. A fungal killing assay indicated that KKOO-NH2 is fungicidal against C. neoformans. The peptide has antifungal activity against multiple major fungal pathogens with a minimum inhibitory concentration (MIC) of 8 μg/mL against C. neoformans and Candida glabrata, 16 μg/mL against Candida albicans and C. auris, and 32 μg/mL against Aspergillus fumigatus. The peptide has low cytotoxicity against host cells based on our hemolysis assays and vesicle leakage assays. Strikingly, the peptide exhibits strong drug synergy with multiple antifungal drugs, including amphotericin B, itraconazole, and caspofungin, depending on the specific species on which the combinations were assayed. The fluorescently labeled peptide was detected to localize to the plasma membrane, likely inhibiting key interactions of Cdc50 with membrane proteins such as P4 ATPases. Cryptococcus cells exposed to sub-MIC of peptide showed increased reactive oxygen species production and intracellular calcium levels, indicating a peptide-induced stress response. Decreased intracellular proliferation within macrophages was observed after 30 min of peptide exposure and 24 h coincubation with macrophages, providing a potential translational mechanism to explore further in vivo. In aggregate, the synergistic activity of our KKOO-NH2 peptide may offer a potential novel candidate for combination therapy with existing antifungal drugs.

Dataset Information

Microbial Metabolite Inspired β-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Publications

Microbial Metabolite Inspired β-Peptide Polymers Displaying Potent and Selective Antifungal Activity.

Similar Datasets

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