β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward

b-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The b-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, beta-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of beta-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of beta-lactam antibiotics, which led to the discovery of beta-lactamase inhibitors (BLIs) and other beta-lactam potentiators. Although there are several successful beta-lactam-beta-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of beta-lactamases have put the quest of new b-lactam potentiators beyond precedence. This review summarizes the success stories of beta-lactamase inhibitors in use, prospective beta-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel b-lactam potentiators. Furthermore, this review discusses the various challenges in taking these beta-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.

Automated summary

Beta-lactam antibiotics are widely used antimicrobial agents, but their misuse has led to the emergence of resistance in clinically important bacterial pathogens. This review summarizes the success stories of beta-lactamase inhibitors and prospective beta-lactam potentiators, and discusses the challenges in translating these potentiation strategies from bench to bedside. Other mechanisms to reduce global antimicrobial resistance burden are also explored.