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Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
- 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.
- Subjects :
- Animals
Antitubercular Agents agonists
Antitubercular Agents chemistry
Biological Products agonists
Biological Products chemistry
Humans
Mice
Mycobacterium tuberculosis drug effects
Oligopeptides blood
Oligopeptides chemistry
Uridine blood
Uridine chemistry
Uridine pharmacology
Antitubercular Agents pharmacology
Biological Products pharmacology
Monosaccharides biosynthesis
Oligopeptides biosynthesis
Oligopeptides pharmacology
Uridine analogs & derivatives
Subjects
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