Polyprodrug Antimicrobials: Remarkable Membrane Damage and Concurrent Drug Release to Combat Antibiotic Resistance of Methicillin-Resistant Staphylococcus aureus.

Abstract

The increased threat of antibiotic resistance has created an urgent need for new strategies. Herein, polyprodrug antimicrobials are proposed to mimic antimicrobial peptides appended with a concurrent drug release property, exhibiting broad-spectrum antibacterial activity and especially high potency to inhibit methicillin-resistant Staphylococcus aureus (MRSA) without inducing resistance. Two series of polyprodrug antimicrobials are fabricated by facile polymerization of triclosan prodrug monomer (TMA) and subsequent quaternization of hydrophilic poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA), affording PDMAEMA-b-PTMA and PQDMA-b-PTMA, respectively. Optimized samples with proper hydrophobic ratio are screened out, which exhibit remarkable bacterial inhibition and low hemolysis toward red blood cells. Furthermore, synergistic antibacterial mechanisms contribute to the bacteria killing, including serious membrane damage, increased out-diffusion of cytosolic milieu across the membrane, and intracellular reductive milieu-mediated triclosan release. No detectable resistance is observed for polyprodrug antimicrobials against MRSA, which is demonstrated to be better than commercial triclosan and vancomycin against in vivo MRSA-infected burn models and a promising approach to the hurdle of antibiotic resistance in biomedicine.