Colistin as a potentiator of anti-TB drug activity against Mycobacterium tuberculosis

Objectives: The mycobacterial cell wall is an effective permeability barrier that limits intracellular concentrations of anti-TB drugs and hampers the success of treatment. We hypothesized that colistin might enhance the efficacy of anti-TB drugs by increasing mycobacterial cell wall permeability. In this study, we investigated the additional effect of colistin on the activity of anti-TB drugs against Mycobacterium tuberculosis in vitro. Methods: The concentration-dependent and time-dependent killing activity of isoniazid, rifampicin or amikacin alone or in combination with colistin against M. tuberculosis H37Rv was determined. Mycobacterial populations with both high and low metabolic activity were studied, and these were characterized by increasing or steady levels of ATP, respectively. Results: With exposure to a single drug, striking differences in anti-TB drug activity were observed when the two mycobacterial populations were compared. The addition of colistin to isoniazid and amikacin resulted in sterilization of the mycobacterial load, but only in the M. tuberculosis population with high metabolic activity. The emergence of isoniazid and amikacin resistance was completely prevented by the addition of colistin. Conclusions: The results of this study emphasize the importance of investigating mycobacterial populations with both high and low metabolic activity when evaluating the efficacy of anti-TB drugs in vitro. This is the first study showing that colistin potentiates the activity of isoniazid and amikacin against M. tuberculosis and prevents the emergence of resistance to anti-TB drugs. These results form the basis for further studies on the applicability of colistin as a potentiator of anti-TB drugs.