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September 2001
Vol. 4, No. 9, p 12
news in brief
Resisting resistance
Microorganisms rapidly evolve to survive environmental challenges. When they are subjected to antibiotics, resistant strains eventually emerge and treatments become less effective. Faced with this challenge, biomedical scientists must constantly investigate new targets to develop new drugs. One such target, beta-lactamase, may just make beta-lactam-based drugs, such as amoxicillin and imipenem, effective again.

beta-Lactam compounds inhibit cell wall biosynthesis, but by hydrolyzing the four-member heterocyclic beta-lactam ring, prokaryotic beta-lactamases neutralize the drugs. To complicate matters, the beta-lactamase genes are often plasmid-borne and pass between bacteria. One metallo-beta-lactamase (MBL), IMP-1, has been found in several clinically important, carbapenem-resistant strains. Although inhibitors can reverse antibiotic resistance, MBLs are a heterogeneous family of enzymes, making development of broad-spectrum inhibitors difficult.

A recent library screen for IMP-1 inhibitors identified a disubstituted succinic acid compound with a low, nanomolar IC50. To understand the essential features of the molecule, Jeffrey Toney and researchers at Merck (Rahway, NJ) synthesized a panel of derivatives with substituents and stereochemical changes (J. Biol. Chem. 2001, 276, 31913– 31918). The study revealed a requirement for 2S,3S stereochemistry and a preference for hydrophobic, aromatic groups. To elucidate the structural basis of these preferences, the researchers solved the crystal structures of IMP-1 bound to the initial lead compound or one of the better derivatives. Comparison of these structures with molecular models of the weaker inhibitors or imipenem docked with IMP-1 revealed that the best compounds are configured such that the carboxylate groups of the inhibitor closely match that of the carboxylate and carbonyl groups of imipenem. These groups coordinate two Zn2+ atoms in the active site. The remaining binding energy derives from van der Waals contacts between the aromatic group and hydrophobic residues lining the active site.

If the stereochemistry is reversed, the inhibitors lose contact with both the Zn2+ and hydrophobic pocket. Derivatives with smaller substituents positioned in the preferred stereochemistry are also poor inhibitors, because these compounds make little contact with the binding pocket despite their ability to coordinate the Zn2+ atoms.

This is an important first step in understanding the critical features of an MBL inhibitor.

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