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
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

951-964

Subventions

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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Auteurs

Samantha L van der Beek (SL)

Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Azul Zorzoli (A)

Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Dundee, UK.

Ebru Çanak (E)

Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Robert N Chapman (RN)

Department of Chemistry, Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, USA.

Kieron Lucas (K)

Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Dundee, UK.

Benjamin H Meyer (BH)

Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Dundee, UK.

Dimitrios Evangelopoulos (D)

Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, UK.

Luiz Pedro S de Carvalho (LPS)

Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, London, UK.

Geert-Jan Boons (GJ)

Department of Chemistry, Complex Carbohydrate Research Center, The University of Georgia, 315 Riverbend Road, Athens, USA.
Department of Medical Chemistry and Chemical Biology, Utrecht Institute Pharmaceutical Science, University Utrecht, Utrecht, 3508 TB, The Netherlands.

Helge C Dorfmueller (HC)

Division of Molecular Microbiology, School of Life Sciences, University of Dundee, Dow Street, DD1 5EH, Dundee, UK.

Nina M van Sorge (NM)

Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

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Classifications MeSH