Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity Against Rifampicin-Resistant Mycobacterium tuberculosis

Abstract

Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy and AIDS related mycobacterial infections. However, prolonged usage of these antibiotics has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate better analogs of rifamycin, we substituted the acyltransferase (AT) domain of module 6 of rifamycin polyketide synthase (rifPKS) with that of module 2 of rapamycin PKS. The resulting mutants (rifAT6::rapAT2) of A. mediterranei S699 produced new rifamycin analogs, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, which contained modification in the polyketide backbone. 24-desmethylrifamycin B was then converted to 24-desmethylrifamycin S, whose structure was confirmed by MS, NMR, and X-ray crystallography. Subsequently, 24-desmethylrifamycin S was converted to 24-desmethylrifampicin, which showed excellent antibacterial activity against several rifampicin-resistant M. tuberculosis strains.This research was originally published in the Journal of Biological Chemistry. Nigam, A., Almabruk, K. H., Saxena, A., Yang, J., Mukherjee, U., Kaur, H., ... & Lal, R. Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis. Journal of Biological Chemistry. 2014. 289:21142-21152. © the American Society for Biochemistry and Molecular Biology. This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by The American Society for Biochemistry and Molecular Biology, Inc., and can be found at: http://www.jbc.org/Keywords: Domain Swapping, Polyketide Synthase, Rifamycin analogs, Multiple Drug Resistant, 24-desmethylrifamyci