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Maksimova EM, Vinogradova DS, Osterman IA, et al. Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation. Front Microbiol. 2021;12:618857doi: 10.3389/fmicb.2021.618857.
Maksimova, E. M., Vinogradova, D. S., Osterman, I. A., Kasatsky, P. S., Nikonov, O. S., Milón, P., Dontsova, O. A., Sergiev, P. V., Paleskava, A., & Konevega, A. L. (2021). Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation. Frontiers in microbiology, 12618857. https://doi.org/10.3389/fmicb.2021.618857
Maksimova, Elena M, et al. "Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation." Frontiers in microbiology vol. 12 (2021): 618857. doi: https://doi.org/10.3389/fmicb.2021.618857
Maksimova EM, Vinogradova DS, Osterman IA, Kasatsky PS, Nikonov OS, Milón P, Dontsova OA, Sergiev PV, Paleskava A, Konevega AL. Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation. Front Microbiol. 2021 Feb 12;12:618857. doi: 10.3389/fmicb.2021.618857. eCollection 2021. PMID: 33643246; PMCID: PMC7907450.
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Front Microbiol. 2021 Feb 12;12:618857. doi: 10.3389/fmicb.2021.618857. eCollection 2021.

Multifaceted Mechanism of Amicoumacin A Inhibition of Bacterial Translation.

Frontiers in microbiology

Elena M Maksimova, Daria S Vinogradova, Ilya A Osterman, Pavel S Kasatsky, Oleg S Nikonov, Pohl Milón, Olga A Dontsova, Petr V Sergiev, Alena Paleskava, Andrey L Konevega

Affiliations

  1. Petersburg Nuclear Physics Institute named by B. P. Konstantinov, NRC "Kurchatov Institute", Gatchina, Russia.
  2. NanoTemper Technologies Rus, St. Petersburg, Russia.
  3. Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.
  4. Department of Chemistry, Lomonosov Moscow State University, Moscow, Russia.
  5. Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia.
  6. Centre for Research and Innovation, Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru.
  7. A. N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
  8. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
  9. Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, Russia.
  10. National Research Centre "Kurchatov Institute", Moscow, Russia.

PMID: 33643246 PMCID: PMC7907450 DOI: 10.3389/fmicb.2021.618857

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.

Copyright © 2021 Maksimova, Vinogradova, Osterman, Kasatsky, Nikonov, Milón, Dontsova, Sergiev, Paleskava and Konevega.

Keywords: amicoumacin A; antibiotic resistance; elongation factor EF-G; initiation; microscale thermophoresis; rapid kinetics; translocation

Conflict of interest statement

AK is a founder of the company NanoTemper Technologies Rus (St. Petersburg, Russia), which provides services and devices based on MST and nanoDSF and represents NanoTemper Technologies GmbH (Germany).

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