Glycosylated Nanotherapeutics with beta-Lactamase Reversible Competitive Inhibitory Activity Reinvigorates Antibiotics against Gram-Negative Bacteria

Sun, HN (Sun, Haonan) 1Yu, YJ (Yu, Yunjian) 1Zhang, YF (Zhang, Yufei) 1Li, J (Li, Jie) 1Cheng, YJ (Cheng, Yijie) 1Huang, SY (Huang, Siyuan) 1Wang, WB (Wang, Wenbo) 1Zhang, XG (Zhang, Xinge) 1

BIOMACROMOLECULES, 2021, 22(7): 2834-2849

DOI 10.1021/acs.biomac.1c00231

Abstract

Antibiotics are currently first-line therapy for bacterial infections. However, the curative effect of antibiotic remedies is limited due to increasingly prevalent bacterial resistance. The strategy to reverse intrinsic acquired drug resistance presents a promising option for reinvigorating antibiotic therapy. Here, we developed a beta-lactamase-inhibiting macromolecule composed of benzoxaborole and dextran for precise transport of beta-lactam antibiotics to strains overexpressing beta-lactamase. Benzoxaborole-derived nanotherapeutics enabled specific recognition and rapid internalization, and the nanotherapeutics with a high affinity toward bacteria distinctly inhibited the catalytic activity of bacterially secreted beta-lactamase by a reversible competitive mechanism. Thus, the system entrapping cefoxitin harbored a significantly enhanced ability to kill drug-resistant Escherichia coli compared to the ability of the drug by specifically overcoming the membrane barrier and acquired resistance mechanism of beta-lactamase overproduction. The reversible competitive nanotherapeutics exhibited a robust therapeutic efficacy in rat wounds infected with drug-resistant bacteria; the efficacy was due to efficient bacterial elimination and collateral benzoxaborole-dependent amelioration of the inflammatory response. The above results offered insights into the facile design of precise macromolecular adjuvants to exclusively reverse the acquired bacterial resistance mechanism and increase the utility of antibiotic therapies against antibiotic-resistant bacterial infections.