Cited by 151Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyInfectious Diseases and Tuberculosis

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

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Dhiman, Rakesh K., Mahapatra, Sebabrata, Slayden, Richard A., Boyne, Melissa E., Lenaerts, Anne, Hinshaw, Jerald C., Angala, Shiva K., Chatterjee, Delphi, Biswas, Kallolmay, Narayanasamy, Prabagaran, Kurosu, Michio, Crick, Dean C.·2009·Molecular Microbiology

DOI 10.1111/j.1365-2958.2009.06625.xPMC PMC4747042

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Abstract

Summary: 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.

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“Because it has recently been shown that both the electron transport system and ATP synthesis are viable anti-TB drug targets (Andries et al., 2005; Weinstein et al., 2005) it was hypothesized that menaquinone synthesis could be critical for mycobacterial survival and the following studies were…”
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BindingDB (2024) · UC San Diego · doi:10.7270/q2dn49fz
BindingDB Entry 50013973: Synthesis, optimization, in vitro and in vivo study of bicyclic substituted amine as MenA inhibitor.
BindingDB (2022) · UC San Diego · doi:10.7270/q2qr51wp
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Authors: 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.
Affiliations: Colorado State University (US)
University of Utah (US)
Corresponding author: Crick, Dean C.
ORCID: Slayden, Richard A.
Chatterjee, Delphi
Biswas, Kallolmay
Narayanasamy, Prabagaran
Kurosu, Michio
Crick, Dean C.
Venue: Molecular Microbiology
Publisher: Wiley
Published: 2009-03-19
Volume: 72
Issue: 1
Pages: 85-97
ISSN: 0950-382X (ISSN-L)
1365-2958
DOI: 10.1111/j.1365-2958.2009.06625.x
PMC: PMC4747042
OpenAlex: W2152545013
Cited by: 146
References: 49
Citations by year: 2026: 5 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 6 · 2020: 11 · 2019: 11 · 2018: 7 · 2017: 11 · 2016: 10 · 2015: 12 · 2014: 14 · 2013: 5 · 2012: 7
FWCI: 5.98
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Molecular Microbiology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute of Allergy and Infectious Diseases (R56AI049151, R01AI055298, AI049151, AI-06357, P01AI057836, R01AI049151, AI055298, AI057836)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Infectious Diseases › Infectious Diseases and Tuberculosis
Keywords: Mycobacterium tuberculosis, non-replicating persistence, latent tuberculosis infection, Middle East and North Africa, electron transport chain, oxygen consumption, bacterial persistence, tuberculosis drug development
MeSH terms: Adenosine Triphosphate, Mycobacterium tuberculosis, Oxygen Consumption, RNA, Bacterial, RNA, Messenger, Gene Expression Regulation, Bacterial, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Vitamin K 2, Electron Transport Chain Complex Proteins, Microbial Viability

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

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