Microbiological evidence for the trisubstituted benzimidazoles targeting MmpL3 in Mycobacterium tuberculosis
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Le résumé fourni par la source
ABSTRACT New anti-tuberculosis (TB) drugs with novel modes of action are in great demand due to the complex treatment regimens as well as the rising number of multidrug-resistant TB cases. We recently re-evaluated a few 2,5,6-trisubstituted benzimidazole derivatives (SBZ) previously demonstrated to have potent antitubercular activity. These compounds displayed favorable MICs and significantly reduced bacterial counts in an acute mouse infection model. Although this antitubercular lead series was initially reported to inhibit mycobacterial cell division, our findings suggest that its primary activity likely involves other cellular targets. By using bacterial cytological profiling, we observed that SBZ-treated Mycobacterium tuberculosis cells exhibit cell wall-damaging phenotypes resembling those caused by known cell wall biosynthesis inhibitors, such as AU1235 and SQ109, that mostly target the membrane protein large 3 (MmpL3). Whole-cell assays further supported the findings by showing activation of the iniBAC operon and accumulation of intracellular ATP. The antitubercular activity of SBZs was tested against engineered mycobacterial strains that have the transcriptionally regulated mmpL3 gene expression, confirming that SBZs engage the MmpL3 target in the cell. Strains with mutations in mmpL3 exhibited either low- or high-level resistance to the SBZs. A molecule docking model is proposed, based on a high-resolution crystal structure of MmpL3, which could be useful in reconciling the inhibition mechanism and suggesting a further development of MmpL3 inhibitor starting with the SBZ scaffold.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Microbiological evidence for the trisubstituted benzimidazoles targeting MmpL3 in <i>Mycobacterium tuberculosis</i>
- Date Crossref
- 01/10/2025
- Éditeur
- American Society for Microbiology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Discovery Institute pays non établi dans la noticeOrganisation à but non lucratif
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Infectious Disease Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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Seattle Children's Research Institute Center for Global Infectious Disease Research pays non établi dans la noticeÉtablissement de santé
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Cornell University pays non établi dans la noticeUniversité ou école supérieure
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Weill Cornell Medicine pays non établi dans la noticeUniversité ou école supérieure
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Linnaeus University pays non établi dans la noticeUniversité ou école supérieure
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University of Washington Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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Department of Microbiology and Immunology pays non établi dans la noticeInstitution
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Linnaeus Bioscience Inc pays non établi dans la noticeEntreprise
Discovery Institute, Infectious Disease Research Institute et Center for Global Infectious Disease Research — Seattle Children's Research Institute, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.