metallolactamases

Metallolactamases, more commonly referred to as metallo-beta-lactamases (MBLs), are a family of zinc-dependent enzymes that inactivate beta-lactam antibiotics by hydrolyzing the beta-lactam ring. They belong to the metallo-beta-lactamase superfamily and are found in a range of Gram-negative bacteria. The enzymes typically require one or two zinc ions at the active site to coordinate a water molecule, which is activated for nucleophilic attack on the beta-lactam carbonyl. The two-zinc mechanism is common among clinically important B1 and B3 enzymes, while some B2 enzymes function with a single zinc ion and may have a narrower activity profile.

MBLs display a broad substrate spectrum, including penicillins, cephalosporins, and many carbapenems, rendering many standard therapies ineffective. Monobactams, such as aztreonam, are often more resistant to hydrolysis by MBLs, though their usefulness can be limited by co-produced beta-lactamases. Genes encoding MBLs are frequently carried on mobile genetic elements, enabling rapid spread across species and genera.

Classification of MBLs follows the Ambler scheme, placing these enzymes in class B. Subclasses B1, B2, and B3 differ in zinc dependency and substrate range. Clinically, MBL-producing pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacterales, and Acinetobacter baumannii pose major treatment challenges.

Detection relies on phenotypic tests that use chelators like EDTA and on molecular assays identifying bla genes (e.g., bla_VIM, bla_IMP, bla_NDM, bla_SPM). Inhibition remains challenging; EDTA inhibits MBls in vitro but is unsuitable clinically. Research continues into specific MBL inhibitors, and therapeutic strategies include combinations such as aztreonam with beta-lactamase inhibitors that do not affect MBLs.