The urgent need for metallo-β-lactamase inhibitors: an unattended global threat

Abstract

Due to their superior tolerability and efficacy, β-lactams are the most potent and prescribed class of antibiotics in the clinic. The emergence of resistance to those antibiotics, mainly due to the production of bacterial enzymes called β-lactamases, has been partially solved by the introduction of β-lactamase inhibitors, which restore the activity of otherwise obsolete molecules. This solution is limited because currently available β-lactamase inhibitors only work against serine β-lactamases, whereas metallo-β-lactamases continue to spread, evolve, and confer resistance to all β-lactams, including carbapenems. Furthermore, the increased use of antibiotics to treat secondary bacterial pneumonia in severely sick patients with COVID-19 might exacerbate the problem of antimicrobial resistance. In this Personal View, we summarise the main advances accomplished in this area of research, emphasise the main challenges that need to be solved, and the importance of research on inhibitors for metallo-B-lactamases amidst the current pandemic.

Figure 1

Evolution and dissemination of NDM-1 carbapenemase (A) Timeline of appearance of NDM variants. Number of amino acid substitutions compared with NDM-1: one (blue), two (green), three (yellow), and five (red). (B) Global dissemination of NDM carbapenemases. Grey sections indicate areas with no reports of NDM carbapenemase. NDM=New Delhi metallo-β-lactamase.

Figure 2

Metallo-β-lactamase inhibitors and reaction intermediate structures (A) Chemical structure of some metallo-β-lactamase inhibitors: the boronates, taniborbactam and QPX7728; the chelator, Aspergillomarasmine A; and the bisthiazolidine, L- bisthiazolidine. (B) Reaction intermediate of meropenem hydrolysis bound to New Delhi metallo-β-lactamase-1.