Antitubercular Triazines: Optimization and Intrabacterial Metabolism

Xin Wang, Daigo Inoyama, Riccardo Russo, Shao Gang Li, Ravindra Jadhav, Thomas P. Stratton, Nisha Mittal, Joseph A. Bilotta, Eric Singleton, Thomas Kim, Steve D. Paget, Richard S. Pottorf, Yong Mo Ahn, Alejandro Davila-Pagan, Srinivasan Kandasamy, Courtney Grady, Seema Hussain, Patricia Soteropoulos, Matthew D. Zimmerman, Hsin Pin HoSteven Park, Véronique Dartois, Sean Ekins, Nancy Connell, Pradeep Kumar, Joel S. Freundlich

Research output: Contribution to journalArticle

Abstract

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO release and InhA inhibition. Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO release and inhibition of the cell wall biosynthesis enzyme InhA.

Original languageEnglish (US)
Pages (from-to)172-185.e11
JournalCell Chemical Biology
Volume27
Issue number2
DOIs
StatePublished - Feb 20 2020
Externally publishedYes

Keywords

  • Bayesian models
  • intrabacterial drug metabolism
  • Mycobacterium tuberculosis
  • nitrofuran
  • triazine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Wang, X., Inoyama, D., Russo, R., Li, S. G., Jadhav, R., Stratton, T. P., Mittal, N., Bilotta, J. A., Singleton, E., Kim, T., Paget, S. D., Pottorf, R. S., Ahn, Y. M., Davila-Pagan, A., Kandasamy, S., Grady, C., Hussain, S., Soteropoulos, P., Zimmerman, M. D., ... Freundlich, J. S. (2020). Antitubercular Triazines: Optimization and Intrabacterial Metabolism. Cell Chemical Biology, 27(2), 172-185.e11. https://doi.org/10.1016/j.chembiol.2019.10.010