Singh, Vinayak ORCID: 0000-0001-9002-2489, Dhar, Neeraj ORCID: 0000-0002-5887-8137, Pato, Janos, Kolly, Gaelle S., Kordulakova, Jana ORCID: 0000-0003-2834-0165, Forbak, Martin, Evans, Joanna C., Szekely, Rita, Rybniker, Jan, Palcekova, Zuzana, Zemanova, Julia, Santi, Isabella, Signorino-Gelo, Francois, Rodrigues, Liliana ORCID: 0000-0002-2094-2666, Vocat, Anthony, Covarrubias, Adrian S., Rengifo, Monica G., Johnsson, Kai ORCID: 0000-0002-8002-1981, Mowbray, Sherry, Buechler, Joseph, Delorme, Vincent, Brodin, Priscille ORCID: 0000-0003-0991-7344, Knott, Graham W., Ainsa, Jose A., Warner, Digby F., Keri, Gyorgy, Mikusova, Katarina, McKinney, John D., Cole, Stewart T., Mizrahi, Valerie and Hartkoorn, Ruben C. (2017). Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria. Mol. Microbiol., 103 (1). S. 13 - 26. HOBOKEN: WILEY-BLACKWELL. ISSN 1365-2958

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Abstract

There is an urgent need to discover new antitubercular 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Singh, VinayakUNSPECIFIEDorcid.org/0000-0001-9002-2489UNSPECIFIED
Dhar, NeerajUNSPECIFIEDorcid.org/0000-0002-5887-8137UNSPECIFIED
Pato, JanosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolly, Gaelle S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kordulakova, JanaUNSPECIFIEDorcid.org/0000-0003-2834-0165UNSPECIFIED
Forbak, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Evans, Joanna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szekely, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rybniker, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palcekova, ZuzanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zemanova, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santi, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Signorino-Gelo, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodrigues, LilianaUNSPECIFIEDorcid.org/0000-0002-2094-2666UNSPECIFIED
Vocat, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Covarrubias, Adrian S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rengifo, Monica G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnsson, KaiUNSPECIFIEDorcid.org/0000-0002-8002-1981UNSPECIFIED
Mowbray, SherryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buechler, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delorme, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodin, PriscilleUNSPECIFIEDorcid.org/0000-0003-0991-7344UNSPECIFIED
Knott, Graham W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ainsa, Jose A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warner, Digby F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keri, GyorgyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mikusova, KatarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKinney, John D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cole, Stewart T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mizrahi, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartkoorn, Ruben C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-243772
DOI: 10.1111/mmi.13535
Journal or Publication Title: Mol. Microbiol.
Volume: 103
Number: 1
Page Range: S. 13 - 26
Date: 2017
Publisher: WILEY-BLACKWELL
Place of Publication: HOBOKEN
ISSN: 1365-2958
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
WALL SYNTHESIS; TUBERCULOSIS; PROTEIN; DIVIVA; WAG31; DIVISION; GROWTH; LOCALIZATION; SMEGMATIS; INTERACTSMultiple languages
Biochemistry & Molecular Biology; MicrobiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24377

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