ArticleMolecular microbiology2017
Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria.
Article in Molecular microbiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 32 citations in OpenAlex.
- Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N'-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives.ChemMedChem · 2025Article
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- Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy.Nature communications · 2024Article
- The Role of Phosphorylation and Acylation in the Regulation of Drug Resistance inBiomedicines · 2022Review
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- Strategies to Combat Multi-Drug Resistance in Tuberculosis.Accounts of chemical research · 2021Review
- Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids.ACS omega · 2021Article
- Structural basis of self-assembly in the lipid-binding domain of mycobacterial polar growth factor Wag31.IUCrJ · 2020Article
- Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets.Frontiers in cellular and infection microbiology · 2020Review
- Article
- Article
- Activation studies with amines and amino acids of the β-carbonic anhydrase encoded by the Rv3273 gene from the pathogenic bacterium Mycobacterium tuberculosis.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- DivIVA concentrates mycobacterial cell envelope assembly for initiation and stabilization of polar growth.Cytoskeleton (Hoboken, N.J.) · 2018Article
- Mycobacteriophages.Microbiology spectrum · 2018Review
- Peptidoglycan in Mycobacteria: chemistry, biology and intervention.Glycoconjugate journal · 2018Review
- Mycobacteriophage Fruitloop gp52 inactivates Wag31 (DivIVA) to prevent heterotypic superinfection.Molecular microbiology · 2018Article
- Article
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31 authors at 12 institutions in 9 countries.
Funding
Abstract
There is an urgent need to discover new anti-tubercular agents with novel mechanisms of action in order to tackle the scourge of drug-resistant tuberculosis. Here, we report the identification of such a molecule - an AminoPYrimidine-Sulfonamide (APYS1) that has potent, bactericidal activity against M. tuberculosis. Mutations in APYS1-resistant M. tuberculosis mapped exclusively to wag31, a gene that encodes a scaffolding protein thought to orchestrate cell elongation. Recombineering confirmed that a Gln201Arg mutation in Wag31 was sufficient to cause resistance to APYS1, however, neither overexpression nor conditional depletion of wag31 impacted M. tuberculosis susceptibility to this compound. In contrast, expression of the wildtype allele of wag31 in APYS1-resistant M. tuberculosis was dominant and restored susceptibility to APYS1 to wildtype levels. Time-lapse imaging and scanning electron microscopy revealed that APYS1 caused gross malformation of the old pole of M. tuberculosis, with eventual lysis. These effects resembled the morphological changes observed following transcriptional silencing of wag31 in M. tuberculosis. These data show that Wag31 is likely not the direct target of APYS1, but the striking phenotypic similarity between APYS1 exposure and genetic depletion of Wag31 in M. tuberculosis suggests that APYS1 might indirectly affect Wag31 through an as yet unknown mechanism.
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