Metallo‐β‐lactamase inhibitors inspired on snapshots from the catalytic mechanism

Abstract

β‐Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β‐lactamases, enzymes that hydrolyze the amide bond present in all β‐lactam compounds. There are several inhibitors against serine‐β‐lactamases (SBLs). Metallo‐β‐lactamases (MBLs) are Zn(II)‐dependent enzymes able to hydrolyze most β‐lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron‐based and thiol‐based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.