79316 20190709135426.0 doi 10.1111/mmi.13535 sideral 97592 ART-2017-97592 eng Singh, Vinayak Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria 2017 Access copy available to the general public Unrestricted 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. info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TB info:eu-repo/grantAgreement/EUR/IEF/PIEF-GA-2012-327219 info:eu-repo/semantics/openAccess All rights reserved http://www.europeana.eu/rights/rr-f/ 3.816 2017 MICROBIOLOGY 35 / 125 = 0.28 2017 Q2 T1 BIOCHEMISTRY & MOLECULAR BIOLOGY 84 / 292 = 0.288 2017 Q2 T1 2.384 2017 Molecular Biology 2017 Q1 Microbiology 2017 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Dhar, Neeraj Pató, János Kolly, Gaëlle S. Korduláková, Jana Forbak, Martin Evans, Joanna C. Székely, Rita Rybniker, Jan Palceková, 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. (orcid)0000-0003-2076-844X Aínsa, José A. Universidad de Zaragoza Warner, Digby F. Kéri, G. Mikušová, Katarina McKinney, John D. Cole, Stewark T. Mizrahi, Valerie Hartkoorn, Ruben C. 1008 630 Universidad de Zaragoza Dpto. Microb.Med.Pr.,Sal.Públ. Área Microbiología 103, 1 (2017), 13-25 Mol. microbiol. MOLECULAR MICROBIOLOGY 0950-382X 703322 http://zaguan.unizar.es/record/79316/files/texto_completo.pdf Postprint 86325 http://zaguan.unizar.es/record/79316/files/texto_completo.jpg?subformat=icon icon Postprint oai:zaguan.unizar.es:79316 articulos driver 2019-07-09-11:29:36 ARTICLE