Combined efficacy of a novel antimicrobial cationic peptide polymer with conventional antibiotics to combat multi-drug resistant pathogens

Abstract

Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year by 2050 and to cost the global economy 100 trillion USD. Novel approaches and alternatives to conventional antibiotics are urgently required to combat antimicrobial resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, CSM5-K5, which targets multidrug resistant (MDR) bacterial species. Here we show that CSM5-K5 exhibits rapid bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin resistant Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to which each organism is otherwise resistant restores sensitivity to the conventional antibiotic. CSM5-K5 alone significantly reduced pre-formed bacterial biofilm by two-four orders of magnitude and, in combination with traditional antibiotics, reduced pre-formed biofilm by more than two-three orders of magnitude at sub inhibitory concentrations. Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment reduced bacterial burdens by one to three orders of magnitude, and acted synergistically with vancomycin and tetracycline to clear VRE and MDR E. coli, respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the three MDR bacteria during 15 days of serial passage. This work demonstrates the feasibility and benefits of using this synthetic cationic peptide as alternative to, or in combination with, traditional antibiotics to treat infections caused by MDR bacteria.