The multiple benefits of second-generation β-lactamase inhibitors in treatment of multidrug-resistant bacteria

The World Health Organisation (WHO) has designated antibiotic resistance as one of the most challenging public health threats of the 21st century. Production of beta-lactamase enzymes by Gram-negative bacteria is the main mechanism of resistance to beta-lactam (BL), the most widely used antibiotic in clinics. In an attempt to neutralise the hydrolytic activity of these enzymes, beta-lactamase inhibitors (BLIs) have been developed. First-generation BLIs include clavulanic acid, sulbactam and tazobactam. However, none of them cover all beta-lactamase classes, and an increasingly wide panel of inhibitor-resistant bacterial strains has developed. Second-generation BLIs function via different mechanisms and were developed by novel scaffolds from which diazabicyclooctane (DBOs) and boronic acids have emerged. In this paper, we provide descriptions of promisor second-generation beta-lactamase inhibitors, such as avibactam, vaborbactam and boronic acids, as well as several BL-BLI combinations that have been designed. While some combinations are now being used in clinical practice, most are presently limited to clinical trials or pre-clinical studies. In this paper, we emphasise the continuous need to develop novel and different BLIs to keep up with the multidrug-resistant bacteria that arise. At this time, however, second-generation BLIs constitute a promising and effective approach.

Automated summary

This paper describes promising second-generation beta-lactamase inhibitors, such as avibactam, vaborbactam, and boronic acids, as well as several BL-BLI combinations. While some combinations are in clinical use, most are still limited to clinical trials or preclinical studies, highlighting the ongoing need for the development of novel BLIs to combat multidrug-resistant bacteria. Second-generation BLIs show promise as an effective approach in addressing antibiotic resistance.