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-67,683 is a novel imidazooxazole that accelerates sterilization in the mouse tuberculosis model. The present study was conducted to determine the activity of OPC-67,683 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-67,683. Unlike isoniazid and rifampicin, whose rates of killing were concentration-independent, OPC-67,683 showed concentration-dependent effects that, at the highest dose levels tested (1.0 microg/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.
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-67,683 is a novel imidazooxazole that accelerates sterilization in the mouse tuberculosis model. The present study was conducted to determine the activity of OPC-67,683 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-67,683. Unlike isoniazid and rifampicin, whose rates of killing were concentration-independent, OPC-67,683 showed concentration-dependent effects that, at the highest dose levels tested (1.0 microg/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 tuberculouspatients and to determine the biological basis of tolerance in the model.
Authors: Jossy van den Boogaard; Gibson S Kibiki; Elton R Kisanga; Martin J Boeree; Rob E Aarnoutse Journal: Antimicrob Agents Chemother Date: 2008-12-15 Impact factor: 5.191
Authors: Chris Greening; F Hafna Ahmed; A Elaaf Mohamed; Brendon M Lee; Gunjan Pandey; Andrew C Warden; Colin Scott; John G Oakeshott; Matthew C Taylor; Colin J Jackson Journal: Microbiol Mol Biol Rev Date: 2016-04-27 Impact factor: 11.056