Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification.
Journal
Molecular microbiology
ISSN: 1365-2958
Titre abrégé: Mol Microbiol
Pays: England
ID NLM: 8712028
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
accepted:
28
12
2018
pubmed:
3
1
2019
medline:
29
1
2020
entrez:
3
1
2019
Statut:
ppublish
Résumé
Biosynthesis of the nucleotide sugar precursor dTDP-L-rhamnose is critical for the viability and virulence of many human pathogenic bacteria, including Streptococcus pyogenes (Group A Streptococcus; GAS), Streptococcus mutans and Mycobacterium tuberculosis. Streptococcal pathogens require dTDP-L-rhamnose for the production of structurally similar rhamnose polysaccharides in their cell wall. Via heterologous expression in S. mutans, we confirmed that GAS RmlB and RmlC are critical for dTDP-L-rhamnose biosynthesis through their action as dTDP-glucose-4,6-dehydratase and dTDP-4-keto-6-deoxyglucose-3,5-epimerase enzymes respectively. Complementation with GAS RmlB and RmlC containing specific point mutations corroborated the conservation of previous identified catalytic residues. Bio-layer interferometry was used to identify and confirm inhibitory lead compounds that bind to GAS dTDP-rhamnose biosynthesis enzymes RmlB, RmlC and GacA. One of the identified compounds, Ri03, inhibited growth of GAS, other rhamnose-dependent streptococcal pathogens as well as M. tuberculosis with an IC
Identifiants
pubmed: 30600561
doi: 10.1111/mmi.14197
pmc: PMC6487966
doi:
Substances chimiques
Anti-Bacterial Agents
0
Nucleoside Diphosphate Sugars
0
Thymine Nucleotides
0
thymidine diphosphate rhamnose
2147-59-3
Hydro-Lyases
EC 4.2.1.-
dTDPglucose 4,6-dehydratase
EC 4.2.1.46
Racemases and Epimerases
EC 5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
951-964Subventions
Organisme : Cancer Research UK
ID : FC001060
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 109357/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001060
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001060
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Molecular Microbiology Published by John Wiley & Sons Ltd.
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