With nearly one-third of the global population infected by Mycobacterium tuberculosis, TB remains a major cause of death (1.7 million in 2006). TB is particularly severe in parts of Asia and Africa where it is often present in
AIDS patients. Difficulties in treatment are exacerbated by the 6-9 month treatment times and numerous side effects. There is significant concern about the multi-
drug-resistant (MDR) strains of TB (0.5 million MDR-TB cases worldwide in 2006). The
rifamycins, long considered a mainstay of TB treatment, were a tremendous breakthrough when they were developed in the 1960's. While the
rifamycins display many admirable qualities, they still have a number of shortfalls including: rapid selection of resistant mutants, hepatotoxicity, a flu-like syndrome (especially at higher doses), potent induction of
cytochromes P450 (CYP) and inhibition of hepatic transporters. This review of the state-of-the-art regarding
rifamycins suggests that it is quite possible to devise improved
rifamycin analogs. Studies showing the potential of shortening the
duration of treatment if higher doses could be tolerated, also suggest that more potent (or less toxic)
rifamycin analogs might accomplish the same end. The improved activity against
rifampin-resistant strains by some analogs promises that further work in this area, especially if the information from co-crystal structures with
RNA polymerase is applied, should lead to even better analogs. The extensive
drug-drug interactions seen with
rifampin have already been somewhat ameliorated with
rifabutin and
rifalazil, and the use of a CYP-induction screening assay should serve to efficiently identify even better analogs. The toxicity due to the flu-like syndrome is an issue that needs effective resolution, particularly for analogs in the
rifalazil class. It would be of interest to profile
rifalazil and analogs in relation to
rifampin,
rifapentine, and
rifabutin in a variety of screens, particularly those that might relate to
hypersensitivity or immunomodulatory processes.