DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization.

Abstract

The flavo-enzyme DprE1 catalyzes a key epimerization step in the decaprenyl-phosphoryl d-arabinose (DPA) pathway, which is essential for mycobacterial cell wall biogenesis and targeted by several new tuberculosis drug candidates. Here, using differential radiolabeling with DPA precursors and high-resolution fluorescence microscopy, we disclose the unexpected extracytoplasmic localization of DprE1 and periplasmic synthesis of DPA. Collectively, this explains the vulnerability of DprE1 and the remarkable potency of the best inhibitors.

• Authors: Miroslav Brecik, Ivana Centárová, Raju Mukherjee, Gaëlle S Kolly, Stanislav Huszár, Adela Bobovská, Emöke Kilacsková, Veronika Mokošová, Zuzana Svetlíková, Michal Šarkan, João Neres, Jana Korduláková, Stewart T Cole, Katarína Mikušová
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 10 Issue 7 Pg. 1631-6 (Jul 17 2015) ISSN: 1554-8937 [Electronic] United States
• PMID: 25906160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antitubercular Agents
• Bacterial Proteins
• Alcohol Oxidoreductases
• DprE1 protein, Mycobacterium tuberculosis

Topics

• Alcohol Oxidoreductases (analysis, metabolism)
• Antitubercular Agents (pharmacology)
• Bacterial Proteins (analysis, metabolism)
• Cell Wall (drug effects, metabolism)
• Humans
• Mycobacterium tuberculosis (cytology, drug effects, enzymology)
• Tuberculosis (drug therapy, microbiology)