Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis
Open accessAbstract
MmpL3, a resistance-nodulation-division (RND) superfamily transporter, has been implicated in the formation of the outer membrane of Mycobacterium tuberculosis ; specifically, MmpL3 is required for the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or outer membrane of M. tuberculosis . Recently, seven series of inhibitors identified by whole-cell screening against M. tuberculosis , including the antituberculosis drug candidate SQ109, were shown to abolish MmpL3-mediated TMM export. However, this mode of action was brought into question by the broad-spectrum activities of some of these inhibitors against a variety of bacterial and fungal pathogens that do not synthesize mycolic acids. This observation, coupled with the ability of three of these classes of inhibitors to kill nonreplicating M. tuberculosis bacilli, led us to investigate alternative mechanisms of action. Our results indicate that the inhibitory effects of adamantyl ureas, indolecarboxamides, tetrahydropyrazolopyrimidines, and the 1,5-diarylpyrrole BM212 on the transport activity of MmpL3 in actively replicating M. tuberculosis bacilli are, like that of SQ109, most likely due to their ability to dissipate the transmembrane electrochemical proton gradient. In addition to providing novel insights into the modes of action of compounds reported to inhibit MmpL3, our results provide the first explanation for the large number of pharmacophores that apparently target this essential inner membrane transporter.
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In general, MmpL3 inhibitors are quite effective in both growth and stasis, although this may be because these drugs dissipate the proton motive force, not because of direct activity against MmpL3, which is probably downregulated in stasis.
“in general, these are quite effective in both growth and stasis, although this may be because these drugs dissipate the proton motive force, not because of direct activity against MmpL3 (ref.159), which is probably downregulated in stasis59.”
From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [159]
Cites
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The mycobacterial cell envelope — a moving target
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- Authors
- Li, W., Upadhyay, A., Fontes, F. L., North, E. J., Wang, Y., Crans, D. C., Grzegorzewicz, A. E., Jones, V., Franzblau, S. G., Lee, R. E., Crick, D. C., & Jackson, M.
- Affiliations
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
- Colorado State University (US)
- St. Jude Children's Research Hospital (US)
- University of Illinois Chicago (US)
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2014-11
- Volume
- 58
- Issue
- 11
- Pages
- 6413-6423
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4249373
- OpenAlex
- W2165243436
- Cited by
- 202
- References
- 4
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 8 · 2023: 13 · 2022: 16 · 2021: 9 · 2020: 22 · 2019: 27 · 2018: 22 · 2017: 22 · 2016: 24 · 2015: 11
- FWCI
- 13.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (R56AI049151, AI049151, AI063054, R01AI049151, R01AI063054)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- MmpL3, Mycobacterium tuberculosis, RND transporters, SQ109, mechanism of action
- MeSH terms
- Adamantane, Anti-Bacterial Agents, Antitubercular Agents, Bacterial Proteins, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Carrier Proteins, Cell Membrane, Cord Factors, Ethylenediamines, Membrane Proteins, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Mycolic Acids, Phenylurea Compounds, Piperazines, Pyrroles, Valinomycin, Tuberculosis, Multidrug-Resistant, Mycobacterium smegmatis, Vitamin K 2, Drug Resistance, Multiple, Bacterial, Membrane Transport Proteins, Proton Ionophores
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