Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis

Oluwabunmi Y. Saliu, Catina Crismale, Stephan K. Schwander, Robert S. Wallis

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Objectives: There is an urgent need for drugs that hasten sterilization in tuberculosis; however, we presently lack indicators of this activity to guide early drug development. We previously described a novel in vitro assay to study mycobacterial phenotypic drug tolerance, in which sterilizing activity could be assessed. OPC-67683 is a novel imidazooxazole that accelerates sterilization in the mouse tuberculosis model. The present study was conducted to determine the activity of OPC-67683 in the in vitro tolerance model using drug-tolerant clinical Mycobacterium tuberculosis strains. Methods: Tolerance was assessed in Bactec radiometric culture as: (i) delayed decline in growth index during 14 days of drug exposure; (ii) shorter time to positivity of subcultures following drug exposure. Results: Four isolates were selected from among 16 surveyed, based on delayed killing by isoniazid and OPC-67683. Unlike isoniazid and rifampicin, whose rates of killing were concentration-independent, OPC-67683 showed concentration-dependent effects that, at the highest dose levels tested (1.0 μg/mL), were superior to isoniazid and equal to rifampicin. Conclusions: The sterilizing activity of OPC-67683 against drug-tolerant M. tuberculosis in the Bactec model is consistent with its activity in mice. Further studies are warranted to examine the effects of OPC-67683 on mycobacterial persistence in tuberculous patients and to determine the biological basis of tolerance in the model.

Original languageEnglish (US)
Pages (from-to)994-998
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Volume60
Issue number5
DOIs
StatePublished - Nov 1 2007

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Keywords

  • Relapse
  • Sterilization
  • Tolerance
  • Tuberculosis

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