The Mechanisms of Action of Ribosome-Targeting Peptide Antibiotics

Polikanov, Y.S.; Aleksashin, Nikolay A.; Beckert, Bertrand; Wilson, Daniel N.

doi:10.3389/fmolb.2018.00048

Cited by 91 publications

(98 citation statements)

References 123 publications

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“…Other 601 antibiotics that exclusively bind to the initiating, but not elongating ribosomes, (e.g. 602 proline-rich antimicrobial peptides (Polikanov et al, 2018)) could also be explored 603 for their utility in mapping translation start sites in bacteria. 604…”

Section: Discussion 566mentioning

confidence: 99%

Retapamulin-assisted ribosome profiling reveals the alternative bacterial proteome

Meydan

Marks

Klepacki

et al. 2019

Preprint

130

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The use of alternative translation initiation sites enables production of more than one protein from a single gene, thereby expanding cellular proteome. Although several such examples have been serendipitously found in bacteria, genome-wide mapping of alternative translation start sites has been unattainable. We found that the antibiotic retapamulin specifically arrests initiating ribosomes at start codons of the genes. Retapamulin-enhanced Ribo-seq analysis (Ribo-RET) not only allowed mapping of conventional initiation sites at the beginning of the genes but, strikingly, it also revealed putative internal start sites in a number of Escherichia coli genes. Experiments demonstrated that the internal start codons can be recognized by the ribosomes and direct translation initiation in vitro and in vivo. Proteins, whose synthesis is initiated at an internal in-frame and out-of-frame start sites, can be functionally important and contribute to the alternative bacterial proteome. The internal start sites my also play regulatory roles in gene expression.

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Section: Discussion 566mentioning

confidence: 99%

Retapamulin-assisted ribosome profiling reveals the alternative bacterial proteome

Meydan

Marks

Klepacki

et al. 2019

Preprint

130

View full text Add to dashboard Cite

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“…The ribosome translates mRNA into protein and represents one of the main antibiotic targets in the bacterial cell. Various steps of protein synthesis are inhibited by natural and synthetic antibacterials (Lin et al, 2018;Polikanov et al, 2018;Wilson, 2009). A number of antibiotics impede initiation of translation by preventing mRNA binding or departure of the ribosome from the start codon (Lin et al, 2018;Polikanov et al, 2018;Wilson, 2009).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide effects of the antimicrobial peptide apidaecin on translation termination

Mangano

Florin

Shao

et al. 2020

Preprint

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Biochemical studies had shown that the antimicrobial peptide apidaecin (Api) inhibits protein synthesis by binding in the nascent peptide exit tunnel and trapping the release factor associated with a terminating ribosome. The mode of Api action in bacterial cells had remained unknown. Genome-wide analysis revealed that Api leads to pronounced ribosome arrest at stop codons and ribosome queuing. In addition, Api causes a dramatic increase of stop codon bypass by ribosomes paused in a pre-release state, resulting in accumulation of proteins with Cterminal extensions. Stop codon bypass occurs in 0-frame, by misincorporating near-cognate aminoacyl-tRNAs, or via frameshifting. Api-mediated pervasive stalling of pre-release ribosomes futilely activates the ribosome rescue systems. Understanding the unique mechanism of Api action in living cells may contribute to development of new treatments for infections and genetic diseases, and research tools for genome exploration.

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“…Nevertheless, interaction with a few ribosomal proteins can be sufficient to inhibit translation and prevent the development of resistance. Already several ribosome-targeting peptide antibiotics are known which interact with different subunits, various ribosomal proteins and can effect initiation, elongation cycle, termination and recycling during protein synthesis (Polikanov et al, 2018). However, none of these peptides have such a broad interaction with the translation machinery as the NCR247based peptides.…”

Section: Discussionmentioning

confidence: 99%

Potent Chimeric Antimicrobial Derivatives of the Medicago truncatula NCR247 Symbiotic Peptide

et al. 2020

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In Rhizobium-legume symbiosis, the bacteria are converted into nitrogen-fixing bacteroids. In many legume species, differentiation of the endosymbiotic bacteria is irreversible, culminating in definitive loss of their cell division ability. This terminal differentiation is mediated by plant peptides produced in the symbiotic cells. In Medicago truncatula more than ∼700 nodule-specific cysteine-rich (NCR) peptides are involved in this process. We have shown previously that NCR247 and NCR335 have strong antimicrobial activity on various pathogenic bacteria and identified interaction of NCR247 with many bacterial proteins, including FtsZ and several ribosomal proteins, which prevent bacterial cell division and protein synthesis. In this study we designed and synthetized various derivatives of NCR247, including shorter fragments and various chimeric derivatives. The antimicrobial activity of these peptides was tested on the ESKAPE bacteria; Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli as a member of Enterobacteriaceae and in addition Listeria monocytogenes and Salmonella enterica. The 12 amino acid long C-terminal half of NCR247, NCR247C partially retained the antimicrobial activity and preserved the multitarget interactions with partners of NCR247. Nevertheless NCR247C became ineffective on S. aureus, P. aeruginosa, and L. monocytogenes. The chimeric derivatives obtained by fusion of NCR247C with other peptide fragments and particularly with a truncated mastoparan sequence significantly increased bactericidal activity and altered the antimicrobial spectrum. The minimal bactericidal concentration of the most potent derivatives was 1.6 µM, which is remarkably lower than that of most classical antibiotics. The killing activity of the NCR247-based chimeric peptides was practically instant. Importantly, these peptides had no hemolytic activity or cytotoxicity on human cells. The properties of these NCR derivatives make them promising antimicrobials for clinical use.

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The Mechanisms of Action of Ribosome-Targeting Peptide Antibiotics

Cited by 91 publications

References 123 publications

Retapamulin-assisted ribosome profiling reveals the alternative bacterial proteome

Retapamulin-assisted ribosome profiling reveals the alternative bacterial proteome

Genome-wide effects of the antimicrobial peptide apidaecin on translation termination

Potent Chimeric Antimicrobial Derivatives of the Medicago truncatula NCR247 Symbiotic Peptide

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