Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA-Dependent and relA-Independent Tolerance to beta-Lactams
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00475286" target="_blank" >RIV/61388963:_____/17:00475286 - isvavai.cz</a>
Result on the web
<a href="http://aac.asm.org/content/61/4/e02173-16.full" target="_blank" >http://aac.asm.org/content/61/4/e02173-16.full</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1128/AAC.02173-16" target="_blank" >10.1128/AAC.02173-16</a>
Alternative languages
Result language
angličtina
Original language name
Subinhibitory Concentrations of Bacteriostatic Antibiotics Induce relA-Dependent and relA-Independent Tolerance to beta-Lactams
Original language description
The nucleotide (p) ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance, and virulence. During amino acid starvation, the Escherichia coli (p) ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p) ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p) ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA. In bacterial cultures, the ribosomal inhibitors thiostrepton, chloramphenicol, and tetracycline all efficiently abolish accumulation of (p) ppGpp induced by the Ile-tRNA synthetase inhibitor mupirocin. This abolishment, however, does not reduce the persister level. In contrast, the combination of dihydrofolate reductase inhibitor trimethoprim with mupirocin, tetracycline, or chloramphenicol leads to ampicillin tolerance. The effect is independent of RelA functionality, specific to beta-lactams, and not observed with the fluoroquinolone norfloxacin. These results refine our understanding of (p) ppGpp's role in antibiotic tolerance and persistence and demonstrate unexpected drug interactions that lead to tolerance to bactericidal antibiotics.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10606 - Microbiology
Result continuities
Project
<a href="/en/project/GA15-11711S" target="_blank" >GA15-11711S: Development of a molecular toolkit for control and investigation of the bacterial stringent response</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Antimicrobial Agents and Chemotherapy
ISSN
0066-4804
e-ISSN
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Volume of the periodical
61
Issue of the periodical within the volume
4
Country of publishing house
US - UNITED STATES
Number of pages
17
Pages from-to
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UT code for WoS article
000397598800032
EID of the result in the Scopus database
2-s2.0-85016798861