Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases
- 17 March 2015
- news
- Published by American Chemical Society (ACS)
- Vol. 58 (9), 3682-3692
- https://doi.org/10.1021/acs.jmedchem.5b00127
Abstract
The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.Keywords
This publication has 25 references indexed in Scilit:
- Carbapenem resistance in Enterobacteriaceae: here is the storm!Trends in Molecular Medicine, 2012
- Features and development of CootActa Crystallographica Section D-Biological Crystallography, 2010
- XDSActa Crystallographica Section D-Biological Crystallography, 2010
- MolProbity: all-atom structure validation for macromolecular crystallographyActa Crystallographica Section D-Biological Crystallography, 2009
- Solving structures of protein complexes by molecular replacement with PhaserActa Crystallographica Section D-Biological Crystallography, 2006
- Recognition and Resistance in TEM β-LactamaseBiochemistry, 2003
- Structure-Based Design Guides the Improved Efficacy of Deacylation Transition State Analogue Inhibitors of TEM-1 β-Lactamase,Biochemistry, 2000
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- Structure-based design of a potent transition state analogue for TEM-1 β-lactamaseNature Structural & Molecular Biology, 1996
- The CCP4 suite: programs for protein crystallographyActa Crystallographica Section D-Biological Crystallography, 1994