[Current status and perspectives on the development of rifamycin derivative antibiotics]

Rifampicin (RFP) was developed as one of the anti-tuberculosis drugs in 1966 and has been used for almost 30 years. Establishment of combination therapy using RFP has been contributing to the treatment/eradication of tuberculosis. A number of rifamycin derivatives, as post RFPs, have been synthesized/developed over the the years. Chemical modification of rifamycins has largely been concentrated on the moiety of naphthalene ring because modification of the ansa chain moiety reduces the activity. In 1992, rifabutin was approved as a preventive drug for MAC infection in AIDS patients in the United States and in European countries. It is noteworthy that rifapentine (RPT) was approved as an anti-tuberculosis drug in 1998 by FDA in the United States. A newly synthesized rifamycin derivative (KRM-1648, rifalazil) possesses a potent activity against both M. Tuberculosis and MAC, and it is now under clinical trial for the treatment of Tuberculosis in the United States. KRM-1648 is metabolized to 30-hydroxy KRM and 25-deacetyl KRM in the body, and its 30-hydroxylation is caused by liver cytochrome P450 3A. It is well known that RFP, RFB and RPT induce liver cytochrome P450 in animals and human, and these accelerate the metabolism of concomitant drugs such as HIV protease inhibitors resulting in lowering their blood levels. While KRM-1648 did not induce liver P450 in animals, but it is not examined yet in human. Clinical study of DOT with intermittent therapy of RPT in combination with INH resulted in the preferable therapeutic effect comparable to the RFP therapy. Since KRM-1648 has a potent activity, a high tissue distribution and a long half-life, it may be also suitable for intermittent therapy. For the future novel anti-tuberculosis drugs and therapy for tuberculosis, it is prerequisite to develop new drugs with a preferable antimicrobial activity, to shorten further the treatment period, and to be effective against multi-drug resistant bacilli. It is expected that more effective novel rifamycin derivatives can be developed with the above view points.