Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation
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Authors
Maksimova, Elena M.Vinogradova, Daria S.
Osterman, Ilya A.
Kasatsky, Pavel S.
Nikonov, Oleg S.
Milón, Pohl
Dontsova, Olga A.
Sergiev, Petr V.
Paleskava, Alena
Konevega, Andrey L.
Issue Date
2021-02-12Keywords
amicoumacin Aantibiotic resistance
elongation factor EF-G
initiation
microscale thermophoresis
rapid kinetics
translocation
Metadata
Show full item recordPublisher
Frontiers Media S.A.Journal
Frontiers in MicrobiologyDOI
10.3389/fmicb.2021.618857Additional Links
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907450/Abstract
Amicoumacin A (Ami) halts bacterial growth by inhibiting the ribosome during translation. The Ami binding site locates in the vicinity of the E-site codon of mRNA. However, Ami does not clash with mRNA, rather stabilizes it, which is relatively unusual and implies a unique way of translation inhibition. In this work, we performed a kinetic and thermodynamic investigation of Ami influence on the main steps of polypeptide synthesis. We show that Ami reduces the rate of the functional canonical 70S initiation complex (IC) formation by 30-fold. Additionally, our results indicate that Ami promotes the formation of erroneous 30S ICs; however, IF3 prevents them from progressing towards translation initiation. During early elongation steps, Ami does not compromise EF-Tu-dependent A-site binding or peptide bond formation. On the other hand, Ami reduces the rate of peptidyl-tRNA movement from the A to the P site and significantly decreases the amount of the ribosomes capable of polypeptide synthesis. Our data indicate that Ami progressively decreases the activity of translating ribosomes that may appear to be the main inhibitory mechanism of Ami. Indeed, the use of EF-G mutants that confer resistance to Ami (G542V, G581A, or ins544V) leads to a complete restoration of the ribosome functionality. It is possible that the changes in translocation induced by EF-G mutants compensate for the activity loss caused by Ami.Type
info:eu-repo/semantics/articleRights
info:eu-repo/semantics/openAccessAttribution-NonCommercial-ShareAlike 4.0 International
Language
engEISSN
1664302XSponsors
Russian Foundation for Basic Researchae974a485f413a2113503eed53cd6c53
10.3389/fmicb.2021.618857
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