ArticleAntimicrobial agents and chemotherapy2012
SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 254 papers.
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254 citing papers in PubMed, 498 citations in OpenAlex.
- Structure, assembly, and mechanism of the MmpL family of transporters.Microbiology and molecular biology reviews : MMBR · 2026Review
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- Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects.Archives of microbiology · 2026Review
- Gaining insights into MmpL3: combining structural and computational approaches to unlock transport and inhibitor-binding mechanisms.Acta crystallographica. Section D, Structural biology · 2026Article
- Ιdentification of SQ109 analogs with enhanced antimicrobial activity against methicillin-resistantAntimicrobial agents and chemotherapy · 2026Article
- Contribution of Proteins to Membrane and Cell Wall Structures in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans.PLoS neglected tropical diseases · 2025Article
- New pyrazole-based derivatives targeting MmpL3 transporter in Mycobacterium tuberculosis: design, synthesis, biological evaluation and molecular docking studies.Molecular diversity · 2025Article
- A bioluminescence-based chemical screen identifies a bactericidal naphthalene scaffold targeting MmpL3 inbioRxiv : the preprint server for biology · 2025Article
- Mycolic Acid-like Lipids Act as Substrates forACS omega · 2025Article
- Common Biological Properties ofACS infectious diseases · 2025Article
- Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action.Cell systems · 2025Article
- Loss ofbioRxiv : the preprint server for biology · 2025Article
- Trehalose catalytic shift inherently enhances phenotypic heterogeneity and multidrug resistance in Mycobacterium tuberculosis.Nature communications · 2025Article
- Mutations in Genes with a Role in Cell Envelope Biosynthesis Render Gram-Negative Bacteria Highly Susceptible to the Anti-Infective Small Molecule D66.Microorganisms · 2025Article
- Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi.ACS infectious diseases · 2025Article
- Investigating the unbinding mechanisms and kinetics of MmpL3 inhibitors: A computational study.Protein science : a publication of the Protein Society · 2025Article
- Tailored phenyl ureas eradicate drug-resistantChemical science · 2025Article
194 more citing papers are in PubMed but not listed here.
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11 authors at 4 institutions in 1 country.
Funding
Abstract
SQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core of Mycobacterium tuberculosis, as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates. In vitro assays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essential mmpL3 gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM.
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