Bactericidal activity of OPC-67683 against drug-tolerant Mycobacterium tuberculosis.
OBJECTIVE
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.
Saliu
Oluwabunmi Y
OY
UMDNJ-New Jersey Medical School, 185 S. Orange Avenue, MSB-185, Newark, NJ, USA.
Crismale
Catina
C
Schwander
Stephan K
SK
Wallis
Robert S
RS
D000995:Antitubercular Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*; D013997:Time Factors
D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles