The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin

Roy, Raktim N; Lomakin, Ivan B.; Gagnon, Matthieu G.; Steitz, Thomas A.

doi:10.1038/nsmb.3031

Cited by 148 publications

(225 citation statements)

References 32 publications

(43 reference statements)

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“…21,22 The large contact area covering the binding sites of chloramphenicol, clindamycin and erythromycin allows them most likely to overcome current resistance mechanisms and to prevent resistance developments by ribosome mutations. 21 Previous studies indicated in vitro half-lives in mouse serum exceeding 3 h, which, together with the low MIC values, suggested high in vivo efficacies. 5,10 This finding was confirmed first for Onc72 using murine E. coli and K. pneumoniae infection models and additionally here for Onc112, which was even more efficient than Onc72.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics andin vivoefficacy of optimized oncocin derivatives

Schmidt

Ostorházi

Wende

et al. 2016

J. Antimicrob. Chemother.

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Objectives: To evaluate the efficacy of antimicrobial peptide Onc112 in a lethal Escherichia coli infection model and the pharmacokinetics of Onc72 and Onc112 administered intravenously or intraperitoneally in mice.Methods: Onc72, Onc112 and their major metabolites in blood, kidneys, liver, brain and urine were quantified by MS using multiple reaction monitoring (MRM) and isotope-labelled peptides.Results: Onc112 rescued all animals when administered intraperitoneally at a dose of 2.5 mg/kg and was thus slightly more efficient than Onc72. The MRM method provided limits of quantification in plasma, urine and kidney, liver and brain homogenates of 7 -80 mg/L, well below the MICs of 2 -4 mg/L. Onc72 and Onc112 reached all organs within 10 min when administered intraperitoneally (5 mg/kg). Their initial concentrations in plasma were 11.9 and 22.6 mg/L, respectively, with elimination t 1/2 values of 14 and 21 min. The peptide concentrations in blood remained above their MICs for 20 min for Onc72 and 80 min for Onc112. The highest peptide concentrations were detected in kidney homogenates, which also contained the highest content of metabolites, indicating, together with the results from analysis of urine samples, that both peptides are cleared through the kidneys.Conclusions: Onc72 and Onc112 reach organs, including the brain, within 10 min after intravenous and intraperitoneal administration. Onc112 remained in blood at concentrations above its MIC for 80 min. The pharmacokinetic profiles explain the high in vivo efficacies in models of systemic infection and indicate the potential use of these agents for the treatment of urinary tract infections.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics andin vivoefficacy of optimized oncocin derivatives

Schmidt

Ostorházi

Wende

et al. 2016

J. Antimicrob. Chemother.

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“…Bac7 and its BODIPY fluorescently labeled derivative [Bac7 -BY] were prepared as previously described (14). Bac5(1-31) and BMAP27 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) were chemically synthesized as previously described (41). Apidaecin 137 and oncocin 112 were generously provided by Ralf Hoffmann (13,42).…”

Section: Methodsmentioning

confidence: 99%

“…All of them invariably have a high number of proline and arginine residues, show similar spectra of activity, including several Gram-negative species, and have similar modes of action. Recently different PR-AMPs, both mammalian Bac7 and insect oncocin and apidaecins, were demonstrated to efficiently bind to different regions of prokaryote ribosomes (9)(10)(11), leading to the inhibition of protein synthesis (12).…”

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confidence: 99%

The Mechanism of Killing by the Proline-Rich Peptide Bac7(1–35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria

Runti

Benincasa

Giuffrida

et al. 2017

Antimicrob Agents Chemother

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Pseudomonas aeruginosa infections represent a serious threat to worldwide health. Proline-rich antimicrobial peptides (PR-AMPs), a particular group of peptide antibiotics, have demonstrated in vitro activity against P. aeruginosa strains. Here we show that the mammalian PR-AMP Bac7(1-35) is active against some multidrug-resistant cystic fibrosis isolates of P. aeruginosa. By confocal microscopy and cytometric analyses, we investigated the mechanism of killing against P. aeruginosa strain PAO1 and three selected isolates, and we observed that the peptide inactivated the target cells by disrupting their cellular membranes. This effect is deeply different from that previously described for PR-AMPs in Escherichia coli and Salmonella enterica serovar Typhimurium, where these peptides act intracellularly after having been internalized by means of the transporter SbmA without membranolytic effects. The heterologous expression of SbmA in PAO1 cells enhanced the internalization of Bac7(1-35) into the cytoplasm, making the bacteria more susceptible to the peptide but at the same time more resistant to the membrane lysis, similarly to what occurs in E. coli. The results evidenced a new mechanism of action for PRAMPs and indicate that Bac7 has multiple and variable modes of action that depend on the characteristics of the different target species and the possibility to be internalized by bacterial transporters. This feature broadens the spectrum of activity of the peptide and makes the development of peptide-resistant bacteria a more difficult process.

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“…[7] Both reports show that residues 1t o1 2o fO nc112 bind to the exit tunnel, including the peptidyl transferase centera nd the binding site of an aminoacylt RNA. In the process, residues 6t o8o f Onc112 overlap with chloramphenicol binding, whereas the subsequentr esidues until position 12 overlap with the binding sites of clindamycin and erythromycin.…”

mentioning

confidence: 98%

Short Proline‐Rich Antimicrobial Peptides Inhibit Either the Bacterial 70S Ribosome or the Assembly of its Large 50S Subunit

et al. 2015

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Short proline-rich antimicrobial peptides (PrAMPs) are a promising class of antibiotics that use novel mechanisms, thus offering the potential to overcome the health threat of multiresistant pathogens. The peptides bind to the bacterial 70S ribosome and can inhibit protein translation. We report that PrAMPs can be divided into two classes, with each class binding to a different site, and thus use different lethal mechanisms. Oncocin-type peptides inhibit protein translation in Escherichia coli by binding to the exit tunnel of the 70S ribosome with half maximal inhibitory concentrations (IC50 values) of around 2 to 6 μmol L(-1), whereas apidaecin-type peptides block the assembly of the large (50S) subunit of the ribosome, resulting in similar IC50 values. The revealed mechanisms should allow the design of new antibiotics to overcome current bacterial resistance mechanisms.

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The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin

Cited by 148 publications

References 32 publications

Pharmacokinetics andin vivoefficacy of optimized oncocin derivatives

Pharmacokinetics andin vivoefficacy of optimized oncocin derivatives

The Mechanism of Killing by the Proline-Rich Peptide Bac7(1–35) against Clinical Strains of Pseudomonas aeruginosa Differs from That against Other Gram-Negative Bacteria

Short Proline‐Rich Antimicrobial Peptides Inhibit Either the Bacterial 70S Ribosome or the Assembly of its Large 50S Subunit

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