Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence

Rakesh K. Dhiman, Sebabrata Mahapatra, Richard A. Slayden, Melissa E. Boyne, Anne Lenaerts, Jerald C. Hinshaw, Shiva K. Angala, Delphi Chatterjee, Kallolmay Biswas, Prabagaran Narayanasamy, Michio Kurosu, Dean C. Crick

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Understanding the basis of bacterial persistence in latent infections is critical for eradication of tuberculosis. Analysis of Mycobacterium tuberculosis mRNA expression in an in vitro model of non-replicating persistence indicated that the bacilli require electron transport chain components and ATP synthesis for survival. Additionally, low μM concentrations of aminoalkoxydiphenylmethane derivatives inhibited both the aerobic growth and survival of non-replicating, persistent M. tuberculosis. Metabolic labelling studies and quantification of cellular menaquinone levels suggested that menaquinone synthesis, and consequently electron transport, is the target of the aminoalkoxydiphenylmethane derivatives. This hypothesis is strongly supported by the observations that treatment with these compounds inhibits oxygen consumption and that supplementation of growth medium with exogenous menaquinone rescued both growth and oxygen consumption of treated bacilli. In vitro assays indicate that the aminoalkoxydiphenylmethane derivatives specifically inhibit MenA, an enzyme involved in the synthesis of menaquinone. Thus, the results provide insight into the physiology of mycobacterial persistence and a basis for the development of novel drugs that enhance eradication of persistent bacilli and latent tuberculosis.

Original languageEnglish (US)
Pages (from-to)85-97
Number of pages13
JournalMolecular Microbiology
Volume72
Issue number1
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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    Dhiman, R. K., Mahapatra, S., Slayden, R. A., Boyne, M. E., Lenaerts, A., Hinshaw, J. C., Angala, S. K., Chatterjee, D., Biswas, K., Narayanasamy, P., Kurosu, M., & Crick, D. C. (2009). Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Molecular Microbiology, 72(1), 85-97. https://doi.org/10.1111/j.1365-2958.2009.06625.x