Article

 

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

Downloadable Content

Download PDF
https://ir.library.oregonstate.edu/concern/articles/mg74qr33k

Descriptions

Attribute NameValues
Creator
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-desmethylrifamycin
Resource Type
DOI
Date Available
Date Issued
Citation
  • Nigam, A., Almabruk, K. H., Saxena, A., Yang, J., Mukherjee, U., Kaur, H., ... & Lal, R. (2014). Modification of Rifamycin Polyketide Backbone Leads to Improved Drug Activity against Rifampicin-resistant Mycobacterium tuberculosis. Journal of Biological Chemistry, 289(30), 21142-21152. doi:10.1074/jbc.M114.572636
Journal Title
Journal Volume
  • 289
Journal Issue/Number
  • 30
Rights Statement
Funding Statement (additional comments about funding)
  • The work at Delhi University was supported by grants from the Department of Biotechnology of the Government of India and Grants from the University of Delhi. Work at Oregon State University was supported by an Exceptional Opportunity Grant from the M.J. Murdock Charitable Trust and the Medical Research Foundation of Oregon. This work was also supported by research fellowships from the Council of Scientific and Industrial Research and University Grants Commission (to A. N., A. S., U. M., P. K., R. K., and P. S.) and a scholarship from the Government of Libya (to K. H. A.).
Publisher
Peer Reviewed
Language
Replaces

Relationships

Parents:

This work has no parents.

Items