Inhibitors of metallo-β-lactamases

The β-lactams are the most successful class of antibiotic drugs but they are vulnerable to inactivation by a growing cadre of β-lactamases that now number more than a thousand variants. β-Lactamases operate by one of two general chemical mechanisms either catalyzing β-lactam ring hydrolysis via a covalent enzyme intermediate through the aegis of an active site serine residue or through a noncovalent Zn-dependent mechanism. The Ser-β-lactamases are currently dominant in the clinic and consequently, there has been great effort to identify inhibitors and to co-formulate these with β-lactam antibiotics. Four such inhibitors are approved for human clinical use and several more are in clinical trials. Metallo-β-lactamases (MBLs), on the other hand, are only now emerging as a global threat and consequently, inhibitor discovery has lagged behind their Ser counterparts. There are now several examples of MBL inhibitors that operate either in a Zn-dependent or Zn-independent mode. The Zn-dependent compounds are more prevalent and some show efficacy in animal models of infection. These compounds function by either acting as an alternate metal ligand, usually displacing a jointly held hydroxide ion shared by enzymes with two Zn²⁺ ions, or alternately by striping Zn from the active site. The increase in the number of candidate MBL inhibitors over recent years reflects the growing clinical challenge of pathogens expressing these enzymes that result in a carbapenem resistance phenotype. While none of these inhibitors are yet in human clinical trials, the increasing importance of these enzymes in drug failure is a strong incentive to continue identifying and characterizing such molecules.