Tran, Anh T., Watson, Emma E., Pujari, Venugopal, Conroy, Trent, Dowman, Luke J., Giltrap, Andrew M., Pang, Angel, Wong, Weng-Ruh, Linington, Roger G., Saunders, Jessica, Charman, Susan A., West, Nicholas P., Bugg, Tim, Tod, Julie, Dowson, Christopher G., Roper, David I., Crick, Dean C., Britton, Warwick J. and Payne, Richard J. (2017) Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nature Communications, 8 . 14414 . doi:10.1038/ncomms14414 ISSN 2041-1723.
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Abstract
Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues were also shown to be nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology R Medicine > RC Internal medicine |
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
| Library of Congress Subject Headings (LCSH): | Tuberculosis -- Infections -- Treatment, Mycobacterium tuberculosis, Drug resistance |
| Journal or Publication Title: | Nature Communications |
| Publisher: | Nature Publishing Group |
| ISSN: | 2041-1723 |
| Official Date: | 1 March 2017 |
| Dates: | Date Event 1 March 2017 Published 21 December 2016 Accepted 23 January 2016 Submitted |
| Volume: | 8 |
| Article Number: | 14414 |
| DOI: | 10.1038/ncomms14414 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Open Access (Creative Commons open licence) |
| Date of first compliant deposit: | 26 January 2017 |
| Date of first compliant Open Access: | 6 July 2017 |
| Funder: | National Health and Medical Research Council (Australia) (NHMRC) , National Institutes of Health. National Institute of Allergy and Infectious Diseases (U.S.) (NIH NIAID), New South Wales Government |
| Grant number: | Project grant 1082533 (NHMRC), Grants AI049151 and AI097550 (NIH NIAID) |
| RIOXX Funder/Project Grant: | Project/Grant ID RIOXX Funder Name Funder ID AI049151 [NIH] National Institutes of Health. National Institute of Allergy and Infectious Diseases AI097550 [NIH] National Institutes of Health. National Institute of Allergy and Infectious Diseases |
| URI: | https://wrap.warwick.ac.uk/85511/ |
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