Outsmarting metallo-β-lactamases by mimicking their natural evolution

Metallo-β-lactamases (MBLs) confer antibiotic resistance to bacteria by hydrolyzing and thus inactivating β-lactam antibiotics. They have raised concerns due to their broad substrate spectra, the absence of clinically useful inhibitors, and their rapid dissemination. The resulting threat to public health is enhanced by their potential to evolve into even more efficient enzymes through mutation. This is based on the assumption that these enzymes are relatively novel and in the beginning of their natural evolution. Their ongoing evolution has been manifested by the isolation of improved enzyme variants from clinical isolates, and improved variants have been generated under controlled laboratory conditions. Our ability to mimic and eventually predict the evolution of MBLs will likely put us into a better position to effectively combat MBL-conferred antibiotic resistance. This review summarizes how various approaches in recent years have brought us closer to that goal.