Mycobacterium tuberculosis ribosomal protein S1 (RpsA) and variants with truncated C-terminal end show absence of interaction with pyrazinoic acid.
Antitubercular Agents
/ metabolism
Bacterial Proteins
/ genetics
Drug Resistance, Multiple, Bacterial
/ genetics
Extensively Drug-Resistant Tuberculosis
/ drug therapy
Humans
Mutation
Mycobacterium tuberculosis
/ drug effects
Pyrazinamide
/ analogs & derivatives
RNA, Bacterial
/ metabolism
Ribosomal Proteins
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 05 2020
20 05 2020
Historique:
received:
23
12
2019
accepted:
29
04
2020
entrez:
21
5
2020
pubmed:
21
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Pyrazinamide (PZA) is an antibiotic used in first- and second-line tuberculosis treatment regimens. Approximately 50% of multidrug-resistant tuberculosis and over 90% of extensively drug-resistant tuberculosis strains are also PZA resistant. Despite the key role played by PZA, its mechanisms of action are not yet fully understood. It has been postulated that pyrazinoic acid (POA), the hydrolyzed product of PZA, could inhibit trans-translation by binding to Ribosomal protein S1 (RpsA) and competing with tmRNA, the natural cofactor of RpsA. Subsequent data, however, indicate that these early findings resulted from experimental artifact. Hence, in this study we assess the capacity of POA to compete with tmRNA for RpsA. We evaluated RpsA wild type (WT), RpsA ∆A438, and RpsA ∆A438 variants with truncations towards the carboxy terminal end. Interactions were measured using Nuclear Magnetic Resonance spectroscopy (NMR), Isothermal Titration Calorimetry (ITC), Microscale Thermophoresis (MST), and Electrophoretic Mobility Shift Assay (EMSA). We found no measurable binding between POA and RpsA (WT or variants). This suggests that RpsA may not be involved in the mechanism of action of PZA in Mycobacterium tuberculosis, as previously thought. Interactions observed between tmRNA and RpsA WT, RpsA ∆A438, and each of the truncated variants of RpsA ∆A438, are reported.
Identifiants
pubmed: 32433489
doi: 10.1038/s41598-020-65173-z
pii: 10.1038/s41598-020-65173-z
pmc: PMC7239899
doi:
Substances chimiques
Antitubercular Agents
0
Bacterial Proteins
0
RNA, Bacterial
0
Ribosomal Proteins
0
ribosomal protein S1
0
tmRNA
0
Pyrazinamide
2KNI5N06TI
pyrazinoic acid
2WB23298SP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8356Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P019978/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P019978/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 099805/Z/12/Z
Pays : United Kingdom
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