Polyaspartate-derived synthetic antimicrobial polymer enhances the activity of rifampicin against multidrug-resistant Pseudomonas aeruginosa infections

Abstract

Infections caused by multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) pose major challenges for treatment due to the acquired, adaptive, and intrinsic resistance developed by the bacteria. Accumulation of mutations, the ability to form biofilms, and the presence of lipopolysaccharides in the outer bacterial membranes are the key mechanisms of drug resistance. Here, we show that a polyaspartate-derived synthetic antimicrobial polymer (SAMP) with a hexyl chain (TAC6) is an effective adjuvant for a hydrophobic antibiotic, rifampicin. Our in vitro studies demonstrated that the combination of TAC6 and rifampicin is effective against clinically isolated multidrug-resistant strains of P. aeruginosa. Membrane permeabilization studies showed that TAC6 allows the permeabilization of bacterial membranes, and the accumulation of rifampicin inside the cells, thereby enhancing its activity. The combination of TAC6 and rifampicin can also degrade the P. aeruginosa biofilms, and therefore can mitigate the adaptive resistance developed by bacteria. We further demonstrated that the combination of TAC6 and rifampicin can clear P. aeruginosa-mediated wound infections effectively. Therefore, our study showed polyaspartate-derived SAMP to be an effective antibiotic adjuvant against P. aeruginosa infections.