Short Synthetic Peptides as Efflux Pump Inhibitors Resensitising Multidrug-Resistant Escherichia coli TG1 and Erwinia amylovora 1189 bacteria

The rapid emergence of multidrug-resistant (MDR) bacteria has motivated researchers to develop new antibiotic agents including antimicrobial adjuvants that resensitise against multidrug-resistance. In this study, four peptides, two 12-mer and two 8-mer derived from the primary structure of human glucose-dependent insulinotropic polypeptide (GIP), were synthesized by solid-phase peptide synthesis (SPPS). These peptides were designated as AO1, AO2, AO3, and AO4, respectively. Their antimicrobial activity was tested against bacteria possessing an AcrAB-TolC efflux pump system, namely Escherichia coli TG1 and Erwinia amylovora 1189. Although the peptides were shown to have no antimicrobial activity, through a synergistic action they each reduced the MIC values of the selected AcrAB-TolC antibiotic substrates by 4 to 8-fold in E. coli TG1 and 4 to 16-fold in E. amylovora 1189. The activity of synthetic peptides as AcrAB-TolC inhibitors in E. coli TG1 and E. amylovora 1189 was tested by intercellular ethidium bromide (EtBr) accumulation assay at different concentrations ranging from 12.5 to 100 µg mL^− 1. When compared to a reference efflux pump inhibitor, the four peptides each demonstrated good inhibitory action, with the optimum being 100 µg mL^− 1. Our results show these to be promising lead peptides for further development as potential antibacterial adjuvants against MDR bacteria.