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JAC Advance Access originally published online on August 29, 2007
Journal of Antimicrobial Chemotherapy 2007 60(5):994-998; doi:10.1093/jac/dkm291
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Oluwabunmi Y. Saliu1, Catina Crismale1, Stephan K. Schwander1 and Robert S. Wallis1,2,*

1 UMDNJ-New Jersey Medical School, 185 S. Orange Avenue, MSB-185, Newark, NJ, USA 2 PPD, 1213 N St. NW, Suite A, WA DC 20005, USA

Received 7 April 2007; returned 19 June 2007; revised 1 July 2007; accepted 11 July 2007

* Corresponding author. Tel: +1-202-360-4784; Fax: +1-919-654-0640; E-mail: robert.wallis{at}columbia.ppdi.com

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.

Keywords: tuberculosis , relapse , sterilization , tolerance


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