Mechanistic insights into translation inhibition by aminoglycoside antibiotic arbekacin.
Anti-Bacterial Agents
/ chemistry
Dibekacin
/ analogs & derivatives
Kinetics
Peptide Elongation Factor G
/ antagonists & inhibitors
Peptide Termination Factors
/ antagonists & inhibitors
Peptides
/ metabolism
Protein Biosynthesis
/ drug effects
Protein Synthesis Inhibitors
/ chemistry
RNA, Messenger
/ metabolism
RNA, Transfer, Amino Acyl
/ metabolism
Ribosomes
/ drug effects
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
09 07 2021
09 07 2021
Historique:
accepted:
26
05
2021
revised:
17
05
2021
received:
27
04
2021
pubmed:
15
6
2021
medline:
29
7
2021
entrez:
14
6
2021
Statut:
ppublish
Résumé
How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from ∼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome. Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by ∼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.
Identifiants
pubmed: 34125898
pii: 6298613
doi: 10.1093/nar/gkab495
pmc: PMC8266624
doi:
Substances chimiques
Anti-Bacterial Agents
0
Peptide Elongation Factor G
0
Peptide Termination Factors
0
Peptides
0
Protein Synthesis Inhibitors
0
RNA, Messenger
0
RNA, Transfer, Amino Acyl
0
Dibekacin
45ZFO9E525
arbekacin
G7V6SLI20L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6880-6892Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Nat Commun. 2015 Jul 30;6:7896
pubmed: 26224058
Medchemcomm. 2016 Jan 1;7(1):11-27
pubmed: 26877861
Structure. 2018 Jun 5;26(6):821-828.e3
pubmed: 29731232
Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):10984-9
pubmed: 22699498
Nat Microbiol. 2017 May 08;2:17068
pubmed: 28481333
Nat Struct Mol Biol. 2007 Aug;14(8):727-32
pubmed: 17660832
Nat Struct Biol. 2000 Feb;7(2):104-7
pubmed: 10655610
Science. 2009 Oct 30;326(5953):694-9
pubmed: 19833919
Biochem J. 1976 Nov 15;160(2):185-94
pubmed: 795428
RNA. 2016 Jan;22(1):10-21
pubmed: 26527791
Nucleic Acids Res. 2009 Feb;37(2):e15
pubmed: 19074194
J Mol Biol. 2003 Mar 21;327(2):369-81
pubmed: 12628244
Nat Chem Biol. 2010 Mar;6(3):244
pubmed: 20154669
J Antibiot (Tokyo). 1973 Nov;26(11):705-7
pubmed: 4209533
RNA Biol. 2021 May 3;:1-13
pubmed: 33938388
J Biol Chem. 2015 Feb 6;290(6):3440-54
pubmed: 25451927
EMBO J. 1999 Jun 1;18(11):3133-8
pubmed: 10357824
Nat Struct Mol Biol. 2011 Oct 23;18(11):1300-2
pubmed: 22020300
Annu Rev Biochem. 2018 Jun 20;87:451-478
pubmed: 29570352
Nat Struct Mol Biol. 2012 Sep;19(9):957-63
pubmed: 22902368
Biol Proced Online. 2004;6:35-54
pubmed: 15103398
Elife. 2019 Jun 07;8:
pubmed: 31172942
Curr Opin Infect Dis. 2013 Dec;26(6):516-25
pubmed: 24141453
Microbiol Rev. 1991 Jun;55(2):316-33
pubmed: 1886524
EMBO J. 1998 Feb 2;17(3):808-16
pubmed: 9451005
Nat Rev Microbiol. 2005 Nov;3(11):870-81
pubmed: 16261170
Antimicrob Agents Chemother. 1983 Nov;24(5):797-802
pubmed: 6362557
Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):13744-13749
pubmed: 27837019
Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E10899-E10908
pubmed: 29208708
Infect Dis Clin North Am. 2016 Jun;30(2):523-537
pubmed: 27208771
Nat Commun. 2019 Jun 12;10(1):2579
pubmed: 31189921
EMBO J. 2008 Jun 18;27(12):1706-17
pubmed: 18497739
Crit Rev Biochem Mol Biol. 2009 Nov-Dec;44(6):393-433
pubmed: 19929179
Arch Biochem Biophys. 1996 Apr 1;328(1):9-16
pubmed: 8638943
J Antibiot (Tokyo). 2018 Mar;71(4):417-424
pubmed: 29402999
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):20964-9
pubmed: 24324168
Science. 2014 Sep 5;345(6201):1188-91
pubmed: 25190797
J Biol Chem. 2021 Jan-Jun;296:100681
pubmed: 33887323
Chembiochem. 2003 Oct 6;4(10):1018-23
pubmed: 14523919
Cold Spring Harb Perspect Med. 2016 Jun 01;6(6):
pubmed: 27252397
Structure. 2020 Oct 6;28(10):1087-1100.e3
pubmed: 32857965
Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15609-15619
pubmed: 32571953
Cell Rep. 2013 Feb 21;3(2):497-508
pubmed: 23416053
Nat Struct Mol Biol. 2017 Dec 7;24(12):1021-1027
pubmed: 29215639
Proc Natl Acad Sci U S A. 2020 May 12;117(19):10271-10277
pubmed: 32341159
Biochem Biophys Res Commun. 1978 Aug 14;83(3):991-7
pubmed: 361042
Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6275-80
pubmed: 24717845
Chem Rev. 2005 Feb;105(2):477-98
pubmed: 15700953
Nature. 2017 Jun 1;546(7656):113-117
pubmed: 28538735
Nat Struct Mol Biol. 2007 Jun;14(6):493-7
pubmed: 17515906
Nat Rev Microbiol. 2014 Jan;12(1):35-48
pubmed: 24336183
Drug Resist Updat. 2010 Dec;13(6):151-71
pubmed: 20833577
Biochimie. 2006 Aug;88(8):1027-31
pubmed: 16806634
Nat Commun. 2021 Mar 23;12(1):1830
pubmed: 33758186
Nat Struct Mol Biol. 2014 Sep;21(9):817-24
pubmed: 25108354
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):
pubmed: 33619089
Nature. 1987 Jun 4-10;327(6121):389-94
pubmed: 2953976
J Mol Biol. 1997 Oct 24;273(2):389-401
pubmed: 9344747
Nat Struct Mol Biol. 2020 Jan;27(1):25-32
pubmed: 31873307
Clin Pharmacol. 2014 Sep 26;6:139-48
pubmed: 25298740
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8603-E8610
pubmed: 28973849
Nucleic Acids Res. 2018 Feb 16;46(3):1362-1374
pubmed: 29267976
J Mol Biol. 2004 Nov 5;343(5):1183-94
pubmed: 15491605
Nature. 2000 Sep 21;407(6802):340-8
pubmed: 11014183
Nucleic Acids Res. 2005 Oct 07;33(17):5677-90
pubmed: 16214802
J Mol Biol. 2015 May 8;427(9):1848-60
pubmed: 25619162
Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):978-83
pubmed: 26755601
ACS Chem Biol. 2013 Jan 18;8(1):105-15
pubmed: 23110460
Annu Rev Biophys. 2018 May 20;47:525-548
pubmed: 29792818
RNA. 2019 Feb;25(2):247-254
pubmed: 30413565