Structural and mechanistic studies on antimicrobial peptides that target multi-drug resistant bacteria

In order to avoid a worst-case scenario, there is a need to develop structurally distinct classes of antibiotics. Herein, the synthesis of cyclic lipopeptides based on the tridecaptins is reported.

In particular, analogues where residues D-Trp5 and Phe9 were substituted for D-Cys and Cys respectively were synthesized and cross-linked with various benzylic linkers of various sizes. Ortho-xylyl, meta-xylyl and para-xylyl cross-linked Oct-TriA1 maintained strong activity against Escherichia coli and other ESKAPE pathogens (including carbapenem-resistant Acinetobacter baumannii). Interestingly, these analogues were resistant to enzymatic degradation in the presence of recently reported D-stereoselective peptidases. <br><br>Secondly, brevicidine represents a promising candidate for further research and development and this ultimately relies on a synthetic route to acquire sufficient material.