Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents
| Autor: | Harvey Rubin, Richard W. Scott, Damian G. Weaver, H. Marie Loughran, Allen B. Reitz, Katie B. Freeman, Michael J. Costanzo, Trevor Selwood, Jay E. Wrobel, Takahiro Yano |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Acinetobacter baumannii
medicine.drug_class Clinical Biochemistry Antibiotics Pharmaceutical Science Antineoplastic Agents Oxidative phosphorylation Microbial Sensitivity Tests Biochemistry Oxidative Phosphorylation Microbiology Small Molecule Libraries Mice Structure-Activity Relationship Oxidoreductase Drug Discovery medicine Animals Humans Quinone Reductases Cytotoxicity Molecular Biology Pathogen Cell Proliferation chemistry.chemical_classification ATP synthase biology Molecular Structure Chemistry Drug discovery Organic Chemistry Liver Neoplasms Hep G2 Cells biology.organism_classification Anti-Bacterial Agents biology.protein NIH 3T3 Cells Molecular Medicine Benzimidazoles Acinetobacter Infections |
| Zdroj: | Bioorganicmedicinal chemistry letters. 25(2) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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