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 domain of module 6 of rifamycin polyketide synthase with that of module 2 of rapamycin polyketide synthase. 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.

• Authors: Aeshna Nigam, Khaled H Almabruk, Anjali Saxena, Jongtae Yang, Udita Mukherjee, Hardeep Kaur, Puneet Kohli, Rashmi Kumari, Priya Singh, Lev N Zakharov, Yogendra Singh, Taifo Mahmud, Rup Lal
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 30 Pg. 21142-52 (Jul 25 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24923585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antitubercular
• Bacterial Proteins
• Polyketide Synthases
• Acyltransferases
• Rifampin

Topics

• Acyltransferases (genetics, metabolism)
• Antibiotics, Antitubercular (biosynthesis)
• Bacterial Proteins (chemistry, genetics, metabolism)
• Drug Resistance, Bacterial
• Mycobacterium tuberculosis
• Polyketide Synthases (chemistry, genetics, metabolism)
• Protein Engineering
• Rifampin (analogs & derivatives, metabolism)