Advancing the therapeutic potential of indoleamides for tuberculosis

Shichun Lun, Rokeya Tasneen, Tridib Chaira, Jozef Stec, Oluseye K. Onajole, Tian J. Yang, Christopher B. Cooper, Khisi Mdluli, Paul J. Converse, Eric L. Nuermberger, V. Samuel Raj, Alan Kozikowski, William R. Bishai

Research output: Contribution to journalArticle

Abstract

Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis. In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.

Original languageEnglish (US)
Article numbere00343-19
JournalAntimicrobial agents and chemotherapy
Volume63
Issue number7
DOIs
StatePublished - 2019

Keywords

  • Chemotherapy
  • Indole-2-carboxamide
  • MmpL3 inhibitor
  • Mouse model
  • Mycobacterium tuberculosis
  • Mycolic acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Lun, S., Tasneen, R., Chaira, T., Stec, J., Onajole, O. K., Yang, T. J., Cooper, C. B., Mdluli, K., Converse, P. J., Nuermberger, E. L., Samuel Raj, V., Kozikowski, A., & Bishai, W. R. (2019). Advancing the therapeutic potential of indoleamides for tuberculosis. Antimicrobial agents and chemotherapy, 63(7), [e00343-19]. https://doi.org/10.1128/AAC.00343-19