2015 SwissTB Award
Dr. med., Dr. nat. med. Jan Rynbiker
Mycobacterium tuberculosis (Mtb) requires protein secretion systems like ESX-1 for intracellular survival and virulence. The major virulence determinant and ESX-1 substrate, EsxA, arrests phagosome maturation and lyses cell membranes, resulting in tissue damage and necrosis that promotes pathogen spread. To identify inhibitors of Mtb protein secretion, we developed a fibroblastsurvival assay exploiting this phenotype and selected molecules that protect host cells from Mtb-induced lysis without being bactericidal in vitro. Hit compounds blocked EsxA secretion and promoted phagosome maturation in macrophages, thus reducing bacterial loads. Target identification studies led to the discovery of BTP15, a benzothiophene inhibitor of the histidine kinase MprB that indirectly regulates ESX-1, and BBH7, a benzyloxybenzylidene-hydrazine compound. BBH7 affects Mtb metal-ion homeostasis and revealed zinc stress as an activating signal for EsxA secretion. This screening approach extends the target spectrum of small molecule libraries and will help tackle the mounting problem of antibiotic-resistant mycobacteria.
Publication
Jan Rybniker 1,2, Jeffrey M. Chen 1, Claudia Sala 1, Ruben C. Hartkoorn 1, Anthony Vocat 1, Andrej Benjak 1, Stefanie Boy-Röttger 1, Ming Zhang 1, Rita Székely 1, Zoltan Greff 3, Laszlo Orfi 3,4, Istvan Szabadkai 3, Janos Pato 3, Görgy Keri 3,5, Stewart T. Cole 1
1Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
21st Department of Internal Medicine, University of Cologne, 50937 Cologne, Germany
3Vichem Chemie Research Ltd., Herman Otto u. 15, 1022 Budapest, Hungary
4Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9, 1092 Budapest, Hungary
5MTA-SE Pathobiochemistry Research Group, Department of Medical Chemistry, Semmelweis University, 1094 Budapest, Hungary