Trehalose-6-Phosphate-Mediated Toxicity Determines Essentiality of OtsB2 in Mycobacterium tuberculosis In Vitro and in Mice. | Academic Article individual record
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 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.

publication outlet

PLoS Pathog

author list (cited authors)
Korte, J., Alber, M., Trujillo, C. M., Syson, K., Koliwer-Brandl, H., Deenen, R., ... Kalscheuer, R.
editor list (cited editors)
Boshoff, H. I.
publication date
2016
keywords
  • Bacterial Proteins
  • Tuberculosis
  • Disease Models, Animal
  • Mice, Inbred C57BL
  • Sugar Phosphates
  • Female
  • Gene Knockdown Techniques
  • Real-Time Polymerase Chain Reaction
  • Trehalose
  • Mycobacterium Tuberculosis
  • Mice
  • Nuclear Magnetic Resonance, Biomolecular
  • Glucosyltransferases
  • Phosphoric Monoester Hydrolases
  • Chromatography, Thin Layer
  • Gene Expression Profiling
  • Animals
  • In Vitro Techniques
altmetric score

15.6

citation count

27

PubMed ID
27936238
identifier
152101SE
Digital Object Identifier (DOI)
start page
e1006043
end page
e1006043
volume
12
issue
12
UN Sustainable Development Goals