4XUZ

Structure of CTX-M-15 bound to RPX-7009 at 1.5 A

Summary for 4XUZ

• Entry DOI: 10.2210/pdb4xuz/pdb
• Related: 4XUX
• Descriptor: Beta-lactamase, CHLORIDE ION, CITRIC ACID, ... (6 entities in total)
• Functional Keywords: hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Klebsiella pneumoniae subsp. pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 29366.28

Authors

Clifton, M.C.,Gardberg, A. (deposition date: 2015-01-26, release date: 2015-04-01, Last modification date: 2024-10-23)

Primary citation

Hecker, S.J.,Reddy, K.R.,Totrov, M.,Hirst, G.C.,Lomovskaya, O.,Griffith, D.C.,King, P.,Tsivkovski, R.,Sun, D.,Sabet, M.,Tarazi, Z.,Clifton, M.C.,Atkins, K.,Raymond, A.,Potts, K.T.,Abendroth, J.,Boyer, S.H.,Loutit, J.S.,Morgan, E.E.,Durso, S.,Dudley, M.N.
Discovery of a Cyclic Boronic Acid beta-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.
J.Med.Chem., 58:3682-3692, 2015

PubMed 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.

PubMed: 25782055
DOI: 10.1021/acs.jmedchem.5b00127

Experimental method

X-RAY DIFFRACTION (1.5 Å)