Outsmarting metallo-beta-lactamases by mimicking their natural evolution.
ABSTRACT Metallo-beta-lactamases (MBLs) confer antibiotic resistance to bacteria by hydrolyzing and thus inactivating beta-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.
Article: Inhibition of a cold-active alkaline phosphatase by imipenem revealed by in silico modeling of metallo-β-lactamase active sites.[show abstract] [hide abstract]
ABSTRACT: We demonstrate the inhibition of the native phosphatase activity of a cold active alkaline phosphatase from Vibrio (VAP) (IC(50) of 44±4 (n=4)μM at pH 7.0 after a 30min preincubation) by a specific β-lactam compound (only by imipenem, and not by ertapenem, meropenem, ampicillin or penicillin G). The homologous scaffold was detected by an in silico analysis that established the spatial and electrostatic congruence of the active site of a Class B2 CphA metallo-β-lactamase from Aeromonas hydrophila to the active site of VAP. The tested β-lactam compounds did not inhibit Escherichia coli or shrimp alkaline phosphatase, which could be ascribed to the lower congruence indicated by CLASP. There was no discernible β-lactamase activity in the tested alkaline phosphatases. This is the first time a scaffold recognizing imipenem in an alkaline phosphatase (VAP) has been demonstrated.FEBS letters 09/2012; 586(20):3710-5. · 3.54 Impact Factor