Abstract
Cathelicidins are an ancient class of antimicrobial peptides (AMPs) with broad spectrum bactericidal activities. In this study, we investigated the diversity and biological activity of cathelicidins of buffalo, a species known for its disease resistance. A series of new homologs of cathelicidin4 (CATHL4), which were structurally diverse in their antimicrobial domain, was identified in buffalo. AMPs of newly identified buffalo CATHL4s (buCATHL4s) displayed potent antimicrobial activity against selected Gram positive (G+) and Gram negative (G-) bacteria. These peptides were prompt to disrupt the membrane integrity of bacteria and induced specific changes such as blebing, budding, and pore like structure formation on bacterial membrane. The peptides assumed different secondary structure conformations in aqueous and membrane-mimicking environments. Simulation studies suggested that the amphipathic design of buCATHL4 was crucial for water permeation following membrane disruption. A great diversity, broad-spectrum antimicrobial action, and ability to induce an inflammatory response indicated the pleiotropic role of cathelicidins in innate immunity of buffalo. This study suggests short buffalo cathelicidin peptides with potent bactericidal properties and low cytotoxicity have potential translational applications for the development of novel antibiotics and antimicrobial peptidomimetics.
Highlights
Almost all eukaryotes including fungi produce antimicrobial peptides (AMPs) as primary defence against bacterial pathogen [1, 2]
The genomic organization of the CATHL locus varies across the species and often represents multiple copies of the gene with subtle or no difference in the Antimicrobial domain (AMD) region (Fig A in S1 File)
The broad-spectrum antimicrobial action of new buCATHL4 variants against both G+ and G- pathogens indicate that they were naturally selected as a component of primary defence in buffalo
Summary
Almost all eukaryotes including fungi produce antimicrobial peptides (AMPs) as primary defence against bacterial pathogen [1, 2]. The mature peptides are unusually rich in certain amino acids such as proline, arginine, and tryptophan and exhibit a variety of secondary structures, i.e., α-helix, β-hairpin, and random coils [4]. These amphipathic peptides bind to the bacterial membrane and kill bacteria by different mechanisms that include formation of water-filled toroidal pore (e.g. LL-37) [5], alteration of cytoplasmic membrane, septum formation, and inhibition of DNA or protein synthesis (e.g. indolicidin) [6]
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