| Summary: | The rise in antimicrobial resistant bacteria is limiting the number of effective treatments for bacterial infections. <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> are two of the pathogens with the highest prevalence of resistance, and with the greatest need for new antimicrobial agents. Combinations of antimicrobial peptides (AMPs) and antibiotics that display synergistic effects have been shown to be an effective strategy in the development of novel therapeutic agents. In this study, we investigated the synergy between the AMP LL-37 and various classes of antibiotics against <i>E. coli</i> and <i>P. aeruginosa</i> strains. Of the six antibiotics tested (ampicillin, tetracycline, ciprofloxacin, gentamicin, aztreonam, and polymyxin B (PMB)), LL-37 displayed the strongest synergy against <i>E. coli</i> MG1655 and <i>P. aeruginosa</i> PAO1 laboratory strains when combined with PMB. Given the strong synergy, the PMB + LL-37 combination was chosen for further examination where it demonstrated synergy against multidrug-resistant and clinical <i>E. coli</i> isolates. Synergy of PMB + LL-37 towards clinical isolates of <i>P. aeruginosa</i> varied and showed synergistic, additive, or indifferent effects. The PMB + LL-37 combination treatment showed significant prevention of biofilm formation as well as eradication of pre-grown <i>E. coli</i> and <i>P. aeruginosa</i> biofilms. Using the <i>Galleria mellonella</i> wax worm model, we showed that the PMB + LL-37 combination treatment retained its antibacterial capacities in vivo. Flow analyses were performed to characterize the mode of action. The results of the present study provide proof of principle for the synergistic response between LL-37 and PMB and give novel insights into a promising new antimicrobial combination against gram-negative planktonic and biofilm cells.
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