Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane
Open accessAbstract
New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
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Knockdown of mmpL3 in M. smegmatis results in accumulation of the mycolate carrier trehalose monomycolate (TMM).
“Knockdown of the mmpL3 gene in M. smegmatis is lethal, and results in reduced levels of outer membrane mycolic acids and the accumulation of the mycolate carrier, trehalose monomycolate (TMM), suggesting a role in mycolic acid transport (150, 151).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [151]
The Results section ('Phenotypic effects of modulating mmpL3 expression'; page unavailable) reports that reduced mmpL3 expression in M. smegmatis decreased TDM formation and mycolic-acid transfer to AG. The Discussion (page unavailable) reports TMM accumulation in AU1235-treated M. tuberculosis, but our copy does not report TMM accumulation following mmpL3 knockdown in M. smegmatis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredKnockdown of mmpL3 in M. smegmatis results in reduced levels of outer membrane mycolic acids.
“Knockdown of the mmpL3 gene in M. smegmatis is lethal, and results in reduced levels of outer membrane mycolic acids and the accumulation of the mycolate carrier, trehalose monomycolate (TMM), suggesting a role in mycolic acid transport (150, 151).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [151]
Knockdown of the mmpL3 gene in M. smegmatis is lethal.
“Knockdown of the mmpL3 gene in M. smegmatis is lethal, and results in reduced levels of outer membrane mycolic acids and the accumulation of the mycolate carrier, trehalose monomycolate (TMM), suggesting a role in mycolic acid transport (150, 151).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [151]
MmpL3 has a role in mycolic acid transport.
“suggesting a role in mycolic acid transport (150, 151)”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [151]
Early inhibitors of MmpL3 were discovered by screening chemical libraries for activity against M. tuberculosis growth and mapping resistance mutations back to the mmpL3 gene.
“Early inhibitors of MmpL3 were discovered by screening chemical libraries for activity against M. tuberculosis growth and mapping resistance mutations back to the mmpL3 gene (151).”
From Mycobacterium smegmatis: The Vanguard of Mycobacterial Research (2023) · cites this paper as [151]
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- Authors
- Grzegorzewicz, A. E., Pham, H., Gundi, V. A. K. B., Scherman, M. S., North, E. J., Hess, T., Jones, V., Gruppo, V., Born, S. E. M., Korduláková, J., Chavadi, S. S., Morisseau, C., Lenaerts, A. J., Lee, R. E., McNeil, M. R., & Jackson, M.
- Affiliations
- Colorado State University (US)
- St. Jude Children's Research Hospital (US)
- Comenius University Bratislava (SK)
- UC Davis Comprehensive Cancer Center (US)
- Corresponding author
- McNeil, Michael R
- Jackson, Mary
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2012-02-19
- Volume
- 8
- Issue
- 4
- Pages
- 334-341
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3307863
- OpenAlex
- W1996907187
- Cited by
- 442
- References
- 48
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 24 · 2023: 33 · 2022: 29 · 2021: 28 · 2020: 46 · 2019: 37 · 2018: 31 · 2017: 33 · 2016: 33 · 2015: 25 · 2014: 36 · 2013: 27 · 2012: 14
- FWCI
- 23.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI085992, RC1AI085992, AI063054, P01AI057836, R01AI063054, AI057836)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, MmpL3, multidrug resistance, trehalose monomycolate, plasma membrane transporters, cell wall biosynthesis, arabinogalactan, mechanism of action
- MeSH terms
- Adamantane, Anti-Bacterial Agents, Bacterial Proteins, Biological Transport, Cell Membrane, Cord Factors, Drug Evaluation, Preclinical, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, Mycolic Acids, Phenylurea Compounds, Trehalose, Drug Resistance, Bacterial, Membrane Transport Proteins, Small Molecule Libraries
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