Simultaneous exploitation of different peptide permeases by combinations of synthetic peptide smugglins can lead to enhanced antibacterial activity

Various synthetic, peptide prodrugs (smugglins) were tested alone and in combination for activity against Escherichia coli. The smugglins may be transported through any of three peptide permeases, and once inside the bacteria are activated by intracellular peptidase action to release their intrinsically impermeant, antibacterial moieties. When each such antibiotic peptide present in a mixture was accumulated via a different permease, synergistic effects could be observed. Synergy was also found when smugglins were combined with other non-peptide antibiotics. The principle of using smugglin combinations could extend the scope of their application, and should minimise the potential problem that can arise from the occurrence of resistant, transport mutants. The smugglin interactions were studied using a modified microtitre plate assay.