title: Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.
abstract: The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxidative phosphorylation (OxPhos) was identified as a novel target for drug discovery research. Consequently, a library of ∼10,000 compounds was screened using a membrane-based ATP synthesis assay. One hit identified was the 2-iminobenzimidazole 1 that inhibited the OxPhos of A. baumannii with a modestly high selectivity against mitochondrial OxPhos, and displayed an MIC of 25μM (17μg/mL) against the pathogen. The 2-iminobenzimidazole 1 was found to inhibit the type 1 NADH-quinone oxidoreductase (NDH-1) of A. baumannii OxPhos by a biochemical approach. Among various derivatives that were synthesized to date, des-hydroxy analog 5 is among the most active with a relatively tight SAR requirement for the N'-aminoalkyl side chain. Analog 5 also showed less cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the potential for this series of compounds as anti-Acinetobacter agents. Additional SAR development and target validation is underway.
authors.affiliation: University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United States. Electronic address: rubinh@upenn.edu.
authors.forename: Harvey
authors.initials: H
authors.lastname: Rubin
authors.affiliation: University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United States.
authors.forename: Trevor
authors.initials: T
authors.lastname: Selwood
authors.affiliation: University of Pennsylvania, 522 Johnson Pavilion, Philadelphia, PA 19104, United States.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yano
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: Damian G
authors.initials: DG
authors.lastname: Weaver
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: H Marie
authors.initials: HM
authors.lastname: Loughran
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Scott
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: Jay E
authors.initials: JE
authors.lastname: Wrobel
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States.
authors.forename: Katie B
authors.initials: KB
authors.lastname: Freeman
authors.affiliation: Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Rd., Doylestown, PA 18902, United States. Electronic address: areitz@fc-cdci.com.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011808:Quinone Reductases / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D054852:Small Molecule Libraries; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases
keywords: 2-Iminobenzimidazole; Acinetobacter baumannii; Anti-infective; Oxidative phosphorylation