Recently, we discovered a novel lipoglycopeptide antibiotic family gausemycin with exceptional structural novelty. We reported two major constituents of the family gausemycins A and B and characterized their antimicrobial activities. Here-in we studied the molecular mechanism of action of gausemycins and report the isolation and structure elucidation of other members of the family gausemycins C, D, E and F, the minor components of the mixture. Antimicrobial activity of the new congeners was found to be lower than that of the previously reported gausemycins A and B, thus suggesting the importance of the free δ amino group of Orn2 and O-glycosylation of Tyr5 for biological function. To disclose the mecha-nism of action of gausemycin family we investigated the antimicrobial activity of the most active compounds, gausemy-cins A and B, in the presence of Ca2+, other metal ions, and phosphate. Gausemycins require significantly higher Ca2+ con-centration for maximum activity than daptomycin, but lower than that required for malacidine and cadasides. Species-specific antimicrobial activity was found upon testing against a wide panel of Gram-positive bacteria. Membranes were previously proposed as a plausible target of gausemycins, therefore, we explored their interactions with various model membrane systems, including lipid bilayers and micelles. The pore-forming ability was found to be dramatically depend-ent on Ca2+ concentration and the lipid composition of the membrane. The NMR study of gausemycin B in zwitterionic and anionic micelles suggested putative structure of the gausemycin/membrane complex and revealed binding of Ca2+ by the macrocyclic domain of the antibiotic.
Gausemycin antibiotic family act via Ca2+-dependent mem-brane targeting
21 November 2022, Version 1
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