التفاصيل البيبلوغرافية
| العنوان: |
Identification of aminopyrimidine‐sulfonamides as potent modulators of Wag31‐mediated cell elongation in mycobacteria |
| المؤلفون: |
Singh, Vinayak, Dhar, Neeraj, Pató, János, Kolly, Gaëlle S., Korduláková, Jana, Forbak, Martin, Evans, Joanna C., Székely, Rita, Rybniker, Jan, Palčeková, Zuzana, Zemanová, Júlia, Santi, Isabella, Signorino‐Gelo, François, Rodrigues, Liliana, Vocat, Anthony, Covarrubias, Adrian S., Rengifo, Monica G., Johnsson, Kai, Mowbray, Sherry, Buechler, Joseph, Delorme, Vincent, Brodin, Priscille, Knott, Graham W., Aínsa, José A., Warner, Digby F., Kéri, György, Mikušová, Katarína, McKinney, John D., Cole, Stewart T., Mizrahi, Valerie, Hartkoorn, Ruben C. |
| المساهمون: |
European Community's Seventh Framework Programme, GSouth African Medical Research Council, National Research Foundation of South Africa, Senior International Research Scholar's grant, Bill & Melinda Gates Foundation, European Commission Marie Curie Fellowship, Slovak Research and Development Agency |
| المصدر: |
Molecular Microbiology ; volume 103, issue 1, page 13-25 ; ISSN 0950-382X 1365-2958 |
| بيانات النشر: |
Wiley |
| سنة النشر: |
2016 |
| المجموعة: |
Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: |
Summary 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. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1111/mmi.13535 |
| الإتاحة: |
https://doi.org/10.1111/mmi.13535Test |
| حقوق: |
http://onlinelibrary.wiley.com/termsAndConditions#vorTest |
| رقم الانضمام: |
edsbas.877BA096 |
| قاعدة البيانات: |
BASE |
