title: Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase.
abstract: With increasing emergence of multi-drug resistant infections, there is a dire need for new classes of compounds that act through unique mechanisms. In this work, we describe the discovery and optimization of a novel series of inhibitors of bacterial methionine aminopeptidase (MAP). Through a high-throughput screening campaign, one azepinone amide hit was found that resembled the native peptide substrate and possessed moderate biochemical potency against three bacterial isozymes. X-ray crystallography was used in combination with substrate-based design to direct the rational optimization of analogs with sub-micromolar potency. The novel compounds presented here represent potent broad-spectrum biochemical inhibitors of bacterial MAP and have the potential to lead to the development of new medicines to combat serious multi-drug resistant infections.
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Rose
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Sushmita D
authors.initials: SD
authors.lastname: Lahiri
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: McKinney
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Albert
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Morningstar
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Shapiro
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Fisher
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. Electronic address: paulrobertfleming@gmail.com.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fleming
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D063208:Methionyl Aminopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001381:Azepines; D004791:Enzyme Inhibitors; D063208:Methionyl Aminopeptidases
keywords: Antibacterial; Azepinone; Drug discovery; Methionine aminopeptidase; Structure-based design