A Fungal Defensin Inhibiting Bacterial Cell-Wall Biosynthesis with Non-Hemolysis and Serum Stability
2022
Sudong Qi | Bin Gao | Shunyi Zhu
Defensins are a class of cationic disulfide-bridged antimicrobial peptides (AMPs) present in many eukaryotic organisms and even in bacteria. They primarily include two distinct but evolutionarily related superfamilies (<i>cis</i> and <i>trans</i>). Defensins in fungi belong to the members of the <i>cis</i>-superfamily with the cysteine-stabilized α-helical and β-sheet fold. To date, many fungal defensin-like peptides (fDLPs) have been found through gene mining of the genome resource, but only a few have been experimentally characterized. Here, we report the structural and functional characterization of Pyronesin4 (abbreviated as Py4), a fDLP previously identified by genomic sequencing of the basal filamentous ascomycete <i>Pyronema confluens</i>. Chemically, synthetic Py4 adopts a native-like structure and exhibits activity on an array of Gram-positive bacteria including some clinical isolates of <i>Staphylococcus</i> and <i>Staphylococcus warneri</i>, a conditioned pathogen inhabiting in human skin. Py4 markedly altered the bacterial morphology and caused cytoplasmic accumulation of the cell-wall synthesis precursor through binding to the membrane-bound Lipid II, indicating that it works as an inhibitor of cell-wall biosynthesis. Py4 showed no hemolysis and high mammalian serum stability. This work identified a new fungal defensin with properties relevant to drug exploration. Intramolecular epistasis between mutational sites of fDLPs is also discussed.
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