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

Authors :
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 TD
Tod J
Dowson CG
Roper DI
Crick DC
Britton WJ
Payne RJ
Source :
Nature communications [Nat Commun] 2017 Mar 01; Vol. 8, pp. 14414. Date of Electronic Publication: 2017 Mar 01.
Publication Year :
2017

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.

Details

Language :
English
ISSN :
2041-1723
Volume :
8
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
28248311
Full Text :
https://doi.org/10.1038/ncomms14414