Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria
| Autor: | János Pató, Jan Rybniker, Gaëlle S. Kolly, Rita Székely, Neeraj Dhar, Zuzana Palčeková, Anthony Vocat, Digby F. Warner, Júlia Zemanová, Monica G Rengifo, Priscille Brodin, John D. McKinney, Adrian Suarez Covarrubias, Vinayak Singh, François Signorino-Gelo, Joseph Buechler, Sherry L. Mowbray, Ruben C. Hartkoorn, José A. Aínsa, Stewart T. Cole, Vincent Delorme, Martin Forbak, Isabella Santi, Joanna C. Evans, Liliana Rodrigues, György Kéri, Katarína Mikušová, Kai Johnsson, Jana Korduláková, Graham Knott, Valerie Mizrahi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Regulation of gene expression Genetics Mutation Tuberculosis 030106 microbiology Wild type Biology medicine.disease_cause medicine.disease biology.organism_classification Microbiology Recombineering 3. Good health Cell biology Mycobacterium tuberculosis 03 medical and health sciences 030104 developmental biology medicine Gene silencing Molecular Biology Gene |
| Zdroj: | Molecular Microbiology. 103:13-25 |
| ISSN: | 0950-382X |
| DOI: | 10.1111/mmi.13535 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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