Universität zu Köln

Rybniker, Jan, Chen, Jeffrey M., Sala, Claudia ORCID: 0000-0003-4031-4648, Hartkoorn, Ruben C., Vocat, Anthony, Benjak, Andrej ORCID: 0000-0003-4522-6575, Boy-Roettger, Stefanie, Zhang, Ming ORCID: 0000-0001-8425-2245, Szekely, Rita, Greff, Zoltan, Orfi, Laszlo ORCID: 0000-0001-6149-2385, Szabadkai, Istvan, Pato, Janos, Keri, Gyoergy and Cole, Stewart T. (2014). Anticytolytic Screen Identifies Inhibitors of Mycobacterial Virulence Protein Secretion. Cell Host Microbe, 16 (4). S. 538 - 549. CAMBRIDGE: CELL PRESS. ISSN 1934-6069

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Abstract

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 fibroblast survival 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rybniker, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Jeffrey M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sala, Claudia UNSPECIFIED orcid.org/0000-0003-4031-4648 UNSPECIFIED Hartkoorn, Ruben C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vocat, Anthony UNSPECIFIED UNSPECIFIED UNSPECIFIED Benjak, Andrej UNSPECIFIED orcid.org/0000-0003-4522-6575 UNSPECIFIED Boy-Roettger, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Ming UNSPECIFIED orcid.org/0000-0001-8425-2245 UNSPECIFIED Szekely, Rita UNSPECIFIED UNSPECIFIED UNSPECIFIED Greff, Zoltan UNSPECIFIED UNSPECIFIED UNSPECIFIED Orfi, Laszlo UNSPECIFIED orcid.org/0000-0001-6149-2385 UNSPECIFIED Szabadkai, Istvan UNSPECIFIED UNSPECIFIED UNSPECIFIED Pato, Janos UNSPECIFIED UNSPECIFIED UNSPECIFIED Keri, Gyoergy UNSPECIFIED UNSPECIFIED UNSPECIFIED Cole, Stewart T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-425864
DOI:	10.1016/j.chom.2014.09.008
Journal or Publication Title:	Cell Host Microbe
Volume:	16
Number:	4
Page Range:	S. 538 - 549
Date:	2014
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1934-6069
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SIGNAL-TRANSDUCTION SYSTEM; PHAGOSOME MATURATION; TUBERCULOSIS; MPRAB; RESISTANCE; ATTENUATION; BIOGENESIS; MECHANISMS; RD1 Multiple languages Microbiology; Parasitology; Virology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42586