Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis

Marie H. Foss, Sovitj Pou, Patrick M. Davidson, Jennifer L. Dunaj, Rolf W. Winter, Sovijja Pou, Meredith H. Licon, Julia K. Doh, Yuexin Li, Jane X. Kelly, Rozalia A. Dodean, Dennis R. Koop, Michael K. Riscoe, Georgiana E. Purdy

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium tuberculosis (Mtb). We report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as TBL-140, which has a minimal inhibitory concentration (MIC99) of 1.2 μg/mL. TBL-140 is effective against drug-resistant Mtb and nonreplicating bacteria. In addition, TBL-140 eliminates expansion of Mtb in cell culture infection assays at its MIC. To define the mechanism of action of this compound, we performed a spontaneous mutant screen and biochemical assays. We determined that TBL-140 treatment affects the proton motive force (PMF) by perturbing the transmembrane potential (Δψ), consistent with a target in the electron transport chain (ETC). As a result, treated bacteria have reduced intracellular ATP levels. We show that TBL-140 exhibits greater metabolic stability than SQ109, a structurally similar compound in clinical trials for treatment of MDR-TB infections. Combined, these results suggest that TBL-140 should be investigated further to assess its potential as an improved therapeutic lead against Mtb.

Original languageEnglish (US)
Pages (from-to)500-508
Number of pages9
JournalACS Infectious Diseases
Volume2
Issue number7
DOIs
StatePublished - Jul 8 2016

Keywords

  • MmpL3
  • antibiotic
  • drug development
  • proton motive force
  • tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases

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  • Cite this

    Foss, M. H., Pou, S., Davidson, P. M., Dunaj, J. L., Winter, R. W., Pou, S., Licon, M. H., Doh, J. K., Li, Y., Kelly, J. X., Dodean, R. A., Koop, D. R., Riscoe, M. K., & Purdy, G. E. (2016). Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis. ACS Infectious Diseases, 2(7), 500-508. https://doi.org/10.1021/acsinfecdis.6b00052