Discovery of Highly Active Derivatives of Daptomycin by Assessing the Effect of Amino Acid Substitutions at Positions 8 and 11 on a Daptomycin Analogue

Daptomycin is an important antibiotic used for treating serious infections caused by Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. Establishing structure–activity relationships of daptomycin is important for developing new daptomycin-based antibiotics with expanded clinical applications and for tackling the ever-increasing problem of antimicrobial resistance. Toward this end, Dap-K6-E12-W13, an active analogue of daptomycin in which the uncommon amino acids in daptomycin are replaced with their common counterparts, was used as a model system for studying the effect of amino acid variation at positions 8 and 11 on in vitro biological activity against a model organism, Bacillus subtilis, and calcium-dependent insertion into model membranes. None of the new peptides were more active than Dap-K6-E12-W13; however, substitution at positions 8 and/or 11 with cationic residues resulted in little or no loss of activity, and some of these analogues were able to insert into model membranes at lower calcium ion concentrations than the parent peptide. Incorporation of these cationic residues into positions 8 and/or 11 of daptomycin itself yielded some derivatives that exhibited lower minimum inhibitory concentrations than daptomycin against B. subtilis 1046 as well as comparable and sometimes superior activity against clinical isolates of MRSA.