"Binding and Deactivation of Beta-Lactam Antibiotics by Metallo-Beta-Lactamases: A Computation Perspective"

Hua Guo
University of New Mexico


Bacterial resistance to b-lactam antibiotics is most commonly con-ferred by b-lactamases, which hydrolytically cleave the amide C-N bond in the b-lactam ring. An important subgroup of b-lactamases contains Zn(II) cofactors. These metallo-b-lactamases pose a potential threat to the treatment of infectious diseases for a number of reasons. First, they have a very broad substrate spectrum, including the latest generations of b-lactam antibiotics. Second, they have been found to spread between species via plasmid and integron-borne mechanisms with an accelerated rate. Finally, there is no clinically effective inhibitor for these metallo-enzymes. In this talk, we will discuss binding and mechanistic studies of metallo-b-lactamases using quantum mechanical/molecular mechanical (QM/MM) methods. In particular, we chose three representative examples of metallo-b-lactamases, namely the monozinc CphA from A. hydrophila, the dizinc L1 from S. maltophilia, and the dizinc IMP-1 from P. aeruginosa. The QM region, which includes the substrate, the zinc ion(s) and its protein ligands, is treated using the self-consistent charge density functional tight binding (SCC-DFTB) model, while the rest of the protein and solvent are treated with molecular mechanical force fields. Density functional theory (DFT) studies have also been carried out with truncated active-site models. We concentrate on the initial nucleophilic sub-stitution step of the catalyzed reaction and elucidate microscopic reaction pathways. These computational studies provide valuable insights that can help to interpret experimental observations and to help designing new inhibitors.


Last Updated: April 03, 2007.