Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Anh T Tran, Emma E. Watson, Venugopal Pujari, Trent Conroy, Luke J. Dowman, Andrew M. Giltrap, Angel Pang, Weng Ruh Wong, Roger G. Linington, Sebabrata Mahapatra, Jessica Saunders, Susan A Charman, Nicholas P. West, Timothy D H Bugg, Julie Tod, Christopher G. Dowson, David I. Roper, Dean C. Crick, Warwick J. Britton, Richard James Payne

Research output: Contribution to journalArticleResearchpeer-review

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 are 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.

Original languageEnglish
Article number14414
Number of pages9
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 1 Mar 2017

Cite this

Tran, A. T., Watson, E. E., Pujari, V., Conroy, T., Dowman, L. J., Giltrap, A. M., ... Payne, R. J. (2017). Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. Nature Communications, 8, [14414]. https://doi.org/10.1038/ncomms14414
Tran, Anh T ; Watson, Emma E. ; Pujari, Venugopal ; Conroy, Trent ; Dowman, Luke J. ; Giltrap, Andrew M. ; Pang, Angel ; Wong, Weng Ruh ; Linington, Roger G. ; Mahapatra, Sebabrata ; Saunders, Jessica ; Charman, Susan A ; West, Nicholas P. ; Bugg, Timothy D H ; Tod, Julie ; Dowson, Christopher G. ; Roper, David I. ; Crick, Dean C. ; Britton, Warwick J. ; Payne, Richard James. / Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. In: Nature Communications. 2017 ; Vol. 8.
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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 are 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.",
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Tran, AT, Watson, EE, Pujari, V, Conroy, T, Dowman, LJ, Giltrap, AM, Pang, A, Wong, WR, Linington, RG, Mahapatra, S, Saunders, J, Charman, SA, West, NP, Bugg, TDH, Tod, J, Dowson, CG, Roper, DI, Crick, DC, Britton, WJ & Payne, RJ 2017, 'Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis' Nature Communications, vol. 8, 14414. https://doi.org/10.1038/ncomms14414

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis. / Tran, Anh T; Watson, Emma E.; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J.; Giltrap, Andrew M.; Pang, Angel; Wong, Weng Ruh; Linington, Roger G.; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A; West, Nicholas P.; Bugg, Timothy D H; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Crick, Dean C.; Britton, Warwick J.; Payne, Richard James.

In: Nature Communications, Vol. 8, 14414, 01.03.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Tran, Anh T

AU - Watson, Emma E.

AU - Pujari, Venugopal

AU - Conroy, Trent

AU - Dowman, Luke J.

AU - Giltrap, Andrew M.

AU - Pang, Angel

AU - Wong, Weng Ruh

AU - Linington, Roger G.

AU - Mahapatra, Sebabrata

AU - Saunders, Jessica

AU - Charman, Susan A

AU - West, Nicholas P.

AU - Bugg, Timothy D H

AU - Tod, Julie

AU - Dowson, Christopher G.

AU - Roper, David I.

AU - Crick, Dean C.

AU - Britton, Warwick J.

AU - Payne, Richard James

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