Inhibitors of metallo- β-lactamases.

Inhibitors of metallo-β-lactamases. Curr Opin Microbiol. 2017 Nov 15;39:96-105 Authors: Rotondo CM, Wright GD Abstract 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 Zn(2+) ions, or alternately by striping Zn from the active site. The increase in the number of can...
Source: Current Opinion in Microbiology - Category: Microbiology Authors: Tags: Curr Opin Microbiol Source Type: research