An atomic perspective on improving daptomycin's activity

Recently, through comprehensive medicinal chemistry efforts, we have found a new daptomycin analogue, termed kynomycin, showing enhanced activity against both methicillin-resistant S. aureus and vancomycin-resistant Enterococcus in vitro and in vivo , with improved pharmacokinetics and lower cytotoxicity than daptomycin . In this study we compared the physicochemical properties of kynomycin with those of daptomycin from an atomic perspective by using Nuclear Magnetic Resonance spectroscopy and Molecular Dynamics simulations. We observed that kynurenine methylation changes daptomycin's key physicochemical properties; its calcium dependent oligomerization efficiency is improved and the modified kynurenine strengths contacts with the lipid tail and tryptophan residues. In addition, it is observed that, compared to daptomycin, kynomycin tetramer is more stable and binds stronger to calcium. The combined experiments provide key clues for the improved antibacterial activity of kynomycin. We expect that this approach will help study the calcium binding and oligomerization features of new calcium dependent peptide antibiotics. • Kynomycin showed improvement in calcium binding and mediated oligomerization. • Daptomycin's methylation affected its local conformation. • Kynomycin's tetramer is more stable and binds stronger to calcium. • NMR-MD approach to study calcium dependent oligomerization of peptide antibiotics