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 β-lactamase enzymes by Gram-negative bacteria is the main mechanism of resistance to β-lactam (BL), the most widely used antibiotic in clinics. In an attempt to neutralise the hydrolytic activity of these enzymes, β-lactamase inhibitors (BLIs) have been developed. First-generation BLIs include clavulanic acid, sulbactam and tazobactam. However, none of them cover all β-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 β-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.