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

Hua Guo
University of New Mexico

ABSTRACT

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.


 

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