Identification of aminopyrimidine‐sulfonamides as potent modulators of Wag31‐mediated cell elongation in mycobacteria
Year: 2016
Type: article
Abstract: 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.
Source: Molecular Microbiology
DOI: 10.1111/mmi.13535
Authors: Vinayak Singh, Neeraj Dhar, János Pató, Gaëlle S. Kolly, Jana Korduláková, Martin Forbak, Joanna C. Evans, Rita Székely, Jan Rybniker, Zuzana Palčeková, Júlia Zemanová, Isabella Santi, François Signorino‐Gelo, Liliana Rodrigues, Anthony Vocat, Adrian S. Covarrubias, Monica G. Rengifo, Kai Johnsson, Sherry Mowbray, Joseph Buechler, Vincent Delorme, Priscille Brodin, Graham W. Knott, José A. Aínsa, Digby F. Warner, György Kéri, Katarína Mikušová, John D. McKinney, Stewart T. Cole, Valerie Mizrahi, Ruben C. Hartkoorn
Institutions: University of Cape Town, Institute of Infectious Disease and Molecular Medicine, École Polytechnique Fédérale de Lausanne, Vichem Chemie (Hungary), University of Cologne, Comenius University Bratislava, Universidad de Zaragoza, Instituto de Salud Carlos III, Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo, Uppsala University, Alere (United States), Centre National de la Recherche Scientifique, Inserm, Université de Lille, Institut Pasteur de Lille, Center for Infection and Immunity of Lille
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,430
OpenAlex ID: W2525498392