title: 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.forename: Aeshna
authors.initials: A
authors.lastname: Nigam
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Almabruk
authors.forename: Anjali
authors.initials: A
authors.lastname: Saxena
authors.forename: Jongtae
authors.initials: J
authors.lastname: Yang
authors.forename: Udita
authors.initials: U
authors.lastname: Mukherjee
authors.forename: Hardeep
authors.initials: H
authors.lastname: Kaur
authors.forename: Puneet
authors.initials: P
authors.lastname: Kohli
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kumari
authors.forename: Priya
authors.initials: P
authors.lastname: Singh
authors.forename: Lev N
authors.initials: LN
authors.lastname: Zakharov
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Singh
authors.forename: Taifo
authors.initials: T
authors.lastname: Mahmud
authors.forename: Rup
authors.initials: R
authors.lastname: Lal
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000904:Antibiotics, Antitubercular / Q000096:biosynthesis*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D009169:Mycobacterium tuberculosis; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015202:Protein Engineering; D012293:Rifampin / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000904:Antibiotics, Antitubercular; D001426:Bacterial Proteins; D048630:Polyketide Synthases; D000217:Acyltransferases; D012293:Rifampin