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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Rubin H,Selwood T,Yano T,Weaver DG,Loughran HM,Costanzo MJ,Scott RW,Wrobel JE,Freeman KB,Reitz AB

doi

10.1016/j.bmcl.2014.11.020

subject

Has Abstract

pub_date

2015-01-15 00:00:00

pages

378-83

issue

2

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(14)01204-9

journal_volume

25

pub_type

杂志文章

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