Broad-Spectrum, Cell Envelope-Active Marinocyclin Antibiotics From a Coral-Derived Bacterium Are Effective Against Colistin-Resistant Bacteria.

Abstract

The marine bacterial genus Aquimarina comprises diverse members with numerous natural product biosynthetic gene clusters but few characterized compounds. Here we report a novel class of lipopeptides with exceptional antibiotic activity, named marinocyclins, isolated from Aquimarina megaterium EL43 associated with the octocoral Eunicella labiata. The major congener marinocyclin A exhibited potent and uniform activity against a broad panel of drug-resistant gram-negative and gram-positive pathogens, including ESKAPE bacteria. The natural product efficiently compromised the outer and inner bacterial membranes, leading to rapid cell permeabilization and lysis. This activity profile was mediated by the ability to bind lipopolysaccharides, anionic phospholipids enriched in bacterial membranes, and peptidoglycan precursors. Eukaryotic cytotoxicity required higher doses than antibacterial activity. Genomic data suggest a nonribosomal biosynthetic origin for marinocyclins. These findings position marinocyclins as a promising new scaffold for antibiotic development and highlight the potential of Aquimarina spp. as a source of novel antibiotics. Further medicinal chemistry optimization of marinocyclins could enhance their prokaryotic selectivity to generate leads for treating infections caused by drug-resistant pathogens.