Action of clofazimine on Mycobacterium avium and Mycobacterium intracellulare

Abstract

Clofazimine is a member of the phenazine pigment family which has been successfully used in chemotherapy against a variety of mycobacteria including M. avium. The presence of clofazimine in growth medium resulted in higher carotenoid pigmentation in M. avium cells. Carotenoid pigments have been shown to quench superoxide radicals supporting the hypothesis that pigmentation possibly protected cells against superoxide. Clofazimine caused the generation of superoxide radicals in M. intracellulare strain LR163 represented by cyanide-resistant oxygen consumption. The amount of oxygen consumed was dependant upon the clofazimine concentration. This supports the hypothesis that clofazimine is antibiotic via its ability to generate toxic oxygen metabolites. Higher catalase activity was found in extracts of cells grown in the presence of a low concentration of clofazimine. At a higher concentration, the amount of catalase and superoxide dismutase activities were lower than the basal level. This finding did not agree with the hypothesis. At this point the reason for the drop in the activities (i.e. lower than basal level) is not known. Clofazimine was mildly synergistic with rifampicin. This result supports hypothesis that the defense mechanism of M. intracellulare to clofazimine was enzymatic. Clofazimine-resistant derivatives of M. intracellulare strain LR163 have been isolated. Their characterization will provide a direct approach towards determining the mode of action of clofazimine in cells.