Bacterial growth kinetics of "M. lufu" in the presence and absence of various drugs alone and in combination. A model for the development of combined chemotherapy against M. leprae?

Abstract

Bacterial growth kinetic studies were performed in a series of potential inhibitors of M. leprae using "M. lufu" as a model strain. Reasons why "M. lufu" is considered to be a better model than M. tuberculosis are presented. The inhibitory power of the single drugs has been quantified, the activity constants are calculated, and the synergistic, additive, or antagonistic behavior of the combinations is evaluated. It is demonstrated that a combination consisting of dapsone (DDS), prothionamide (PTH), isoniazid (INH), and rifampin (RAMP) is a very powerful inhibitor of "M. lufu" and prevents or delays the development of resistance under the experimental conditions described. This finding is in agreement with the therapeutic effect of this combination (Isoprodian + rifampin) achieved in a leprosy eradication program on the Island of Malta. Whereas there is no direct proof that "M. lufu" is the best suitable model for drug evaluation against M. leprae, there is, however, nothing in the presented results which is against this model, especially as the actions of DDS and PTH or RAMP is concerned. A new combination of DDS with trimethoprim (TMP) or TMP derivatives has also been studied and seems to be a promising candidate. In addition, a technique is described to differentiate between bacteriostatic and bactericidal action of the tested inhibitors against "M. lufu."