Unacylated tridecaptin A1 acts as an effective sensitiser of Gram-negative bacteria to other antibiotics

• H-TriA enhances activity of rifampicin and vancomycin against Gram-negative pathogens.
• H-TriA is a tridecaptin (lipopeptide) derivative missing its N-terminal lipid tail.
• H-TriA itself has low cytotoxicity, haemolytic activity and antimicrobial activity.
• H-TriA is readily made by chemical synthesis and is stable in plasma.

A derivative of the linear cationic lipopeptide tridecaptin A1 missing the N-terminal lipophilic acyl group, termed H-TriA1, is devoid of antimicrobial activity but is extremely effective at sensitising Gram-negative bacteria to certain antibiotics. H-TriA1 has low cytotoxicity compared with the natural peptide and in low concentrations it can substantially lower the minimum inhibitory concentration (MIC) of some antibiotics against strains of Escherichia coli, Campylobacter jejuni and Klebsiella pneumoniae. In particular, the MIC of rifampicin was lowered 256–512-fold against K. pneumoniae strains using low concentrations of H-TriA1. H-TriA1 does not exert its synergistic effect through partial membrane lysis, but does bind to model bacterial membranes in a manner akin to the natural peptide. Formation of this stable secondary structure on the outer membrane may account for the observed synergistic activity.