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DOI: 10.1055/s-0034-1382583
Modification of rifamycin polyketide backbone leads to improved drug activity against rifampicin-resistant M. tuberculosis
Rifamycin B, a product of Amycolatopsis mediterranei S699, is the precursor of clinically used antibiotics that are effective against tuberculosis, leprosy & AIDS related mycobacterial infections. Prolonged usage of these antibiotics, however, has resulted in the emergence of rifamycin resistant strains of Mycobacterium tuberculosis. As part of our effort to generate novel rifamycin analogues with improved biological properties, we substituted the acyltransferase domain of module 6 of rifamycin polyketide synthases (PKS) with that of module 2 of rapamycin PKS. The resulting mutant produces rifamycin analogues, 24-desmethylrifamycin B and 24-desmethylrifamycin SV, in which modifications take place 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 used to produce 24-desmethylrifampicin, which showed comparable or better antibacterial activity than rifampicin against several pathogenic bacteria, including rifampicin-resistant M. tuberculosis.