The 7-phenyl benzoxaborole series is active against Mycobacterium tuberculosis

• Published in: Tuberculosis (Edinburgh, Scotland) Scotland), 2018-01, Vol.108, p.96-98
• Main Authors: Korkegian, Aaron, O'Malley, Theresa, Xia, Yi, Zhou, Yasheen, Carter, David S., Sunde, Bjorn, Flint, Lindsay, Thompson, Dean, Ioerger, Thomas R., Sacchettini, Jim, Alley, M.R.K., Parish, Tanya
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Boron Compounds - chemistry; Boron Compounds - pharmacology; Boron Compounds - toxicity; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - toxicity; Clinical outcomes; Cytotoxicity; Dose-Response Relationship, Drug; Drug resistance; Drug Resistance, Bacterial; Eukaryotes; Humans; Macrophages; Microbial Sensitivity Tests; Mutants; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Mycobacterium tuberculosis - genetics; NADH; NADH dehydrogenase; NADH Dehydrogenase - antagonists & inhibitors; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Nicotinamide adenine dinucleotide; Proteins; Resistant mutant; THP-1 Cells; Toxicity; Tuberculosis
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2017.11.003

We identified a series of novel 7-phenyl benzoxaborole compounds with activity against Mycobacterium tuberculosis. Compounds had a range of activity with inhibitory concentrations (IC90) as low as 5.1 μM and no cytotoxicity against eukaryotic cells (IC50 > 50 μM). Compounds were active against intracellular mycobacteria cultured in THP-1 macrophages. We isolated and characterized resistant mutants with mutations in NADH dehydrogenase (Ndh) or the regulatory protein Mce3R. Mutations suggest that Ndh may be the target of this series.