pH‐Responsive Polymer–Drug Conjugate: An Effective Strategy to Combat the Antimicrobial Resistance

Abstract An urgent need for developing new antimicrobial approaches has emerged due to the imminent threat of antimicrobial‐resistant (AMR) pathogens. Bacterial infection can induce a unique microenvironment with low pH, which can be employed to trigger drug release and activation. Here, a pH‐responsive polymer–drug conjugate (PDC) capable of combating severe infectious diseases and overcoming AMR is reported. The PDC is made of a unique biodegradable and biocompatible cationic polymer Hex‐Cys‐DET and streptomycin, a model antibiotic. The two components show strong antimicrobial synergy since the polymer can induce pores on the bacterial wall/membrane, thus significantly enhancing the transport of antibiotics into the bacteria and bypassing the efflux pump. The PDC is neutralized for enhanced biocompatibility under physiological conditions but becomes positively charged while releasing the antibiotic in infected tissues due to the low pH. Additionally, the polymer contains disulfide bonds in its main chain, which makes it biodegradable in mammalian cells and thus reducing the cytotoxicity. The PDC can effectively penetrate bacterial biofilms and be taken up by mammalian cells, thereby minimizing biofilm‐induced AMR and intracellular infections. The PDC exhibits remarkable antimicrobial activity in three in vivo infection models, demonstrating its broad‐spectrum antimicrobial capability and great potency in eliminating AMR infections.