A UNIQUE MECHANISM OF GLYCINE-SPECIFIC INHIBITION OF BACTERIAL TRANSLATION BY BOTTROMYCIN A2

Мұқаба

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Тек жазылушылар үшін

Аннотация

The rise of antimicrobial resistance among pathogenic bacteria poses a critical challenge to modern medicine, highlighting an urgent need for novel therapeutic agents. Bottomycin A2 (BotA2) is a promising candidate for future drug development, demonstrating potent activity against clinically relevant pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and Mycoplasma species, although its molecular mechanism of action has remained unclear until now. Here, we demonstrate that BotA2 inhibits bacterial translation with unique context specificity determined by the mRNA coding sequence. Using high-throughput toe-printing coupled with deep sequencing (Toe-seq analysis), we show that BotA2 induces ribosome pausing predominantly when a glycine codon enters the A-site of the ribosome, regardless of the codon identities in the P- and E-sites. Our biochemical and biophysical data indicate that BotA2 specifically arrests glycine-delivering ternary complexes on the ribosome, thereby preventing full accommodation of incoming Gly-tRNAGly within the peptidyl transferase center. Altogether, our findings uncover a previously undescribed mechanism of translation inhibition, driven by the context-specific immobilization of ternary complexes on elongating ribosomes.

Авторлар туралы

I. Volynkina

Lomonosov Moscow State University; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology

Email: petya@genebee.msu.su
119234 Moscow, Russia; 121205 Moscow, Russia

A. Grachev

Molecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute"

188300 Gatchina, Leningrad Region, Russia

A. Livenskyi

Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology; Institute of Gene Biology, Russian Academy of Sciences; Lomonosov Moscow State University

121205 Moscow, Russia; 119334 Moscow, Russia; 119234 Moscow, Russia

D. Yagoda

Lomonosov Moscow State University

119234 Moscow, Russia

P. Kasatsky

Molecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute"

188300 Gatchina, Leningrad Region, Russia

O. Tolicheva

Molecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute"

188300 Gatchina, Leningrad Region, Russia

E. Komarova

Lomonosov Moscow State University; A. N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University

119234 Moscow, Russia; 119234 Moscow, Russia

A. Tupikin

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences

630090 Novosibirsk, Novosibirsk Region, Russia

V. Alferova

A. N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

119234 Moscow, Russia; 117997 Moscow, Russia

A. Karakchieva

Lomonosov Moscow State University

119234 Moscow, Russia

A. Nikandrova

Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology; A. N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University; Lomonosov Moscow State University

121205 Moscow, Russia; 119234 Moscow, Russia; 119234 Moscow, Russia

M. Biryukov

Lomonosov Moscow State University

119234 Moscow, Russia

Y. Zakalyukina

Lomonosov Moscow State University

119234 Moscow, Russia

L. Dorofeeva

All-Russian Collection of Microorganisms, G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Pushchino Scientific Center for Biological Research, Russian Academy of Sciences

142290 Pushchino, Moscow Region, Russia

Y. Ikhalaynen

Lomonosov Moscow State University

119234 Moscow, Russia

I. Rodin

Lomonosov Moscow State University

119234 Moscow, Russia

D. Lukianov

Lomonosov Moscow State University; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology

119234 Moscow, Russia; 121205 Moscow, Russia

M. Kabilov

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences

630090 Novosibirsk, Novosibirsk Region, Russia

E. Paleskava

Molecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute"; Institute of Biomedical Systems and Biotechnologies, St. Petersburg Peter the Great Polytechnic University

188300 Gatchina, Leningrad Region, Russia; 195251 Saint Petersburg, Russia

A. Konevega

Molecular and Radiation Biophysics Division, Petersburg Nuclear Physics Institute named by B. P. Konstantinov of National Research Center "Kurchatov Institute"; Institute of Biomedical Systems and Biotechnologies, St. Petersburg Peter the Great Polytechnic University; Centre for Nano, Bio, Info, Cognitive, and Social Sciences and Technologies (NBICS Center), National Research Center "Kurchatov Institute"

Email: konevega.al@pnpi.nrcki.ru
188300 Gatchina, Leningrad Region, Russia; 195251 Saint Petersburg, Russia; 123182 Moscow, Russia

P. Sergiev

Lomonosov Moscow State University; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology; A. N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University

119234 Moscow, Russia; 121205 Moscow, Russia; 119234 Moscow, Russia

O. Dontsova

Lomonosov Moscow State University; Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology; A. N. Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

119234 Moscow, Russia; 121205 Moscow, Russia; 119234 Moscow, Russia; 117997 Moscow, Russia

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