Universität zu Köln

Korte, Jan, Alber, Marina, Trujillo, Carolina M., Syson, Karl, Koliwer-Brandl, Hendrik, Deenen, Rene, Koehrer, Karl, DeJesus, Michael A., Hartman, Travis, Jacobs, William R., Jr., Bornemann, Stephen ORCID: 0000-0001-5930-9473, Ioerger, Thomas R., Ehrt, Sabine and Kalscheuer, Rainer ORCID: 0000-0002-3378-2067 (2016). Trehalose-6-Phosphate-Mediated Toxicity Determines Essentiality of OtsB2 in Mycobacterium tuberculosis In Vitro and in Mice. PLoS Pathog., 12 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a Delta otsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Korte, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Alber, Marina UNSPECIFIED UNSPECIFIED UNSPECIFIED Trujillo, Carolina M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Syson, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Koliwer-Brandl, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Deenen, Rene UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehrer, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED DeJesus, Michael A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartman, Travis UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacobs, William R., Jr. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bornemann, Stephen UNSPECIFIED orcid.org/0000-0001-5930-9473 UNSPECIFIED Ioerger, Thomas R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehrt, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Kalscheuer, Rainer UNSPECIFIED orcid.org/0000-0002-3378-2067 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-255047
DOI:	10.1371/journal.ppat.1006043
Journal or Publication Title:	PLoS Pathog.
Volume:	12
Number:	12
Date:	2016
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TREHALOSE BIOSYNTHESIS; ALPHA-GLUCAN; CANDIDA-ALBICANS; GENE-EXPRESSION; PHOSPHATASE; GLGE; DISRUPTION; PATHWAY; RNA; METABOLISM Multiple languages Microbiology; Parasitology; Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25504