title: Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.
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.
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.affiliation: ‡Molsoft L.L.C., 11199 Sorrento Valley Road, San Diego, California 92121, United States.
authors.forename: Maxim
authors.initials: M
authors.lastname: Totrov
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Gavin C
authors.initials: GC
authors.lastname: Hirst
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Lomovskaya
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Griffith
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: King
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Tsivkovski
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Sun
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Sabet
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Tarazi
authors.affiliation: §Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Clifton
authors.affiliation: §Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States.
authors.forename: Kateri
authors.initials: K
authors.lastname: Atkins
authors.affiliation: §Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Raymond
authors.affiliation: §Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States.
authors.forename: Kristy T
authors.initials: KT
authors.lastname: Potts
authors.affiliation: §Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Abendroth
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Loutit
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Morgan
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Durso
authors.affiliation: †Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001897:Boronic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015780:Carbapenems / Q000494:pharmacology; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001618:beta-Lactamases
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001897:Boronic Acids; D015780:Carbapenems; D006573:Heterocyclic Compounds, 1-Ring; C000599945:RPX7009; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; C063912:carbapenemase