The designer proline-rich antibacterial peptide A3-APO is effective against systemic Escherichia coli infections in different mouse models

Szabó, Dóra; Ostorházi, Eszter; Binas, Annegret; Rozgonyi, Ferenc; Kocsis, Béla; Cassone, Marco; Wade, John D.; Nolte, Oliver; Ötvös, László

doi:10.1016/j.ijantimicag.2009.10.015

Cited by 62 publications

(63 citation statements)

References 25 publications

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“…The mechanism of action of PR-AMPs, such as Bac7 and other proline-rich peptides, has previously been well depicted in E. coli and Salmonella enterica serovar Typhimurium (22,28). PR-AMPs cross the plasma membrane, exploiting the inner membrane protein SbmA (23,29), and enter the cytoplasm, where they inhibit vital functions such as protein synthesis (12).…”

Section: Mode Of Action Of Bac7(1-35) Against P Aeruginosamentioning

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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Section: Mode Of Action Of Bac7(1-35) Against P Aeruginosamentioning

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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“…The peptide dimer A3-APO (Table I) and its monomeric in vivo metabolite are among the most active HDP in a wide spectrum of bacterial infection models in mice [97]. Although the APO peptides have only weak activity against Acinetobacter baumannii in vitro, when administered either intravenously or intramuscularly to mice infected with a carbapenem-resistant A. baumannii strain, the peptides significantly reduce bacterial load and increase survival compared with mice treated with higher doses of imipenem [98].…”

Section: Designer Proline-arginine-rich Antibioticsmentioning

confidence: 99%

Immunomodulatory effects of anti-microbial peptides

Ötvös¹

2016

Acta Microbiologica et Immunologica Hungarica

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Anti-microbial peptides (AMPs) were originally thought to exert protecting actions against bacterial infection by disintegrating bacterial membranes. Upon identification of internal bacterial targets, the view changed and moved toward inhibition of prokaryote-specific biochemical processes. However, the level of none of these activities can explain the robust efficacy of some of these peptides in animal models of systemic and cutaneous infections. A rapidly growing panel of reports suggests that AMPs, now called host-defense peptides (HDPs), act through activating the immune system of the host. This includes recruitment and activation of macrophages and mast cells, inducing chemokine production and altering NF-κB signaling processes. As a result, both pro-and anti-inflammatory responses are elevated together with activation of innate and adaptive immunity mechanisms, wound healing, and apoptosis. HDPs sterilize the systemic circulation and local injury sites significantly more efficiently than pure single-endpoint in vitro microbiological or biochemical data would suggest and actively aid recovering from tissue damage after or even without bacterial infections. However, the multiple and, often opposing, immunomodulatory functions of HDPs require exceptional care in therapeutic considerations.

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“…Insect-derived PrAMPs, e.g., abaecin, apidaecin, drosocin, and pyrrhocoricin (4,5,7,23), are typically 20 to 35 residues long and have a relatively high proportion of basic amino acid residues. Recently, several laboratories have started to optimize PrAMPs for clinical applications, e.g., A3-APO (25), Bac7 (12), oncocin (16), and Api88 (9), which proved successful in rodent infection models (1,15,32). Mechanistically, PrAMPs and the related designer peptides enter the bacteria and kill them, most likely by inhibiting the 70-kDa bacterial chaperone DnaK (17,20,24).…”

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confidence: 99%

Intracellular Toxicity of Proline-Rich Antimicrobial Peptides Shuttled into Mammalian Cells by the Cell-Penetrating Peptide Penetratin

Hansen

Schäfer

Knappe

et al. 2012

Antimicrob Agents Chemother

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The designer proline-rich antibacterial peptide A3-APO is effective against systemic Escherichia coli infections in different mouse models

Cited by 62 publications

References 25 publications

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

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

Immunomodulatory effects of anti-microbial peptides

Intracellular Toxicity of Proline-Rich Antimicrobial Peptides Shuttled into Mammalian Cells by the Cell-Penetrating Peptide Penetratin

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