000079316 001__ 79316
000079316 005__ 20190709135426.0
000079316 0247_ $$2doi$$a10.1111/mmi.13535
000079316 0248_ $$2sideral$$a97592
000079316 037__ $$aART-2017-97592
000079316 041__ $$aeng
000079316 100__ $$aSingh, Vinayak
000079316 245__ $$aIdentification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria
000079316 260__ $$c2017
000079316 5060_ $$aAccess copy available to the general public$$fUnrestricted
000079316 5203_ $$aThere 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.
000079316 536__ $$9info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TB$$9info:eu-repo/grantAgreement/EUR/IEF/PIEF-GA-2012-327219
000079316 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000079316 590__ $$a3.816$$b2017
000079316 591__ $$aMICROBIOLOGY$$b35 / 125 = 0.28$$c2017$$dQ2$$eT1
000079316 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b84 / 292 = 0.288$$c2017$$dQ2$$eT1
000079316 592__ $$a2.384$$b2017
000079316 593__ $$aMolecular Biology$$c2017$$dQ1
000079316 593__ $$aMicrobiology$$c2017$$dQ1
000079316 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000079316 700__ $$aDhar, Neeraj
000079316 700__ $$aPató, János
000079316 700__ $$aKolly, Gaëlle S.
000079316 700__ $$aKorduláková, Jana
000079316 700__ $$aForbak, Martin
000079316 700__ $$aEvans, Joanna C.
000079316 700__ $$aSzékely, Rita
000079316 700__ $$aRybniker, Jan
000079316 700__ $$aPalceková, Zuzana
000079316 700__ $$aZemanová, Júlia
000079316 700__ $$aSanti, Isabella
000079316 700__ $$aSignorino-Gelo, François
000079316 700__ $$aRodrigues, Liliana
000079316 700__ $$aVocat, Anthony
000079316 700__ $$aCovarrubias, Adrian S.
000079316 700__ $$aRengifo, Monica G.
000079316 700__ $$aJohnsson, Kai
000079316 700__ $$aMowbray, Sherry
000079316 700__ $$aBuechler, Joseph
000079316 700__ $$aDelorme, Vincent
000079316 700__ $$aBrodin, Priscille
000079316 700__ $$aKnott, Graham W.
000079316 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José A.$$uUniversidad de Zaragoza
000079316 700__ $$aWarner, Digby F.
000079316 700__ $$aKéri, G.
000079316 700__ $$aMikušová, Katarina
000079316 700__ $$aMcKinney, John D.
000079316 700__ $$aCole, Stewark T.
000079316 700__ $$aMizrahi, Valerie
000079316 700__ $$aHartkoorn, Ruben C.
000079316 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología
000079316 773__ $$g103, 1 (2017), 13-25$$pMol. microbiol.$$tMOLECULAR MICROBIOLOGY$$x0950-382X
000079316 8564_ $$s703322$$uhttps://zaguan.unizar.es/record/79316/files/texto_completo.pdf$$yPostprint
000079316 8564_ $$s86325$$uhttps://zaguan.unizar.es/record/79316/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000079316 909CO $$ooai:zaguan.unizar.es:79316$$particulos$$pdriver
000079316 951__ $$a2019-07-09-11:29:36
000079316 980__ $$aARTICLE