Tag Archives: M33

New publication: Into the killing activity of an antimicrobial peptide against antibiotic-resistant K. pneumoniae

Investigations into the killing activity of an antimicrobial peptide active against extensively antibiotic-resistant K. pneumoniae and P. aeruginosa

Abstracts

SET-M33 is a multimeric antimicrobial peptide active against Gram-negative bacteria in vitro and in vivo. Insights into its killing mechanism could elucidate correlations with selectivity.

Grpahical abstract of the publication: Investigations into the killing activity of an antimicrobial peptide active against extensively antibiotic-resistant K. pneumoniae and P. aeruginosa

SET-M33 showed concentration-dependent bactericidal activity against colistin-susceptible and resistant isolates of P. aeruginosa and K. pneumoniae. Scanning and transmission microscopy studies showed that SET-M33 generated cell blisters, blebs, membrane stacks and deep craters in K. pneumoniae and P. aeruginosa cells. NMR analysis and CD spectra in the presence of sodium dodecyl sulfate micelles showed a transition from an unstructured state to a stable α-helix, driving the peptide to arrange itself on the surface of micelles.

SET-M33 kills Gram-negative bacteria after an initial interaction with bacterial LPS. The molecule becomes then embedded in the outer membrane surface, thereby impairing cell function. This activity of SET-M33, in contrast to other similar antimicrobial peptides such as colistin, does not generate resistant mutants after 24 h of exposure, non-specific interactions or toxicity against eukaryotic cell membranes, suggesting that SET-M33 is a promising new option for the treatment of Gram-negative antibiotic-resistant infections.

Authors

Hessel van der Weide, Jlenia Brunetti, Alessandro Pini, Luisa Bracci, Chiara Ambrosini, Pietro Lupetti, Eugenio Paccagnini, Mariangela Gentile, Andrea Bernini, Neri Niccolai, Denise Vermeulen-de Jongh, Irma A.J.M. Bakker-Woudenberg, Wil H.F. Goessens, John P. Hays, Chiara Falciani

Sources

H. van der Weide et al. Investigations into the killing activity of an antimicrobial peptide active against extensively antibiotic-resistant K. pneumoniae and P. aeruginosa. Biochimica et Biophysica Acta (BBA) – Biomembranes, 2017. DOI: 10.1016/j.bbamem.2017.06.001.

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Meet us at ECCMID 2017

PneumoNP partners will attend ECCMID 2017 in Vienna, Austria, from 22-25th April 2017.

ECCMID2017

ECCMID is a major event for experts of infectious diseases and clinical microbiology. A wide range of these topics will be discussed during symposia and poster sessions.

Several PneumoNP partners attend ECCMID 2017. They will present and discuss the latest results of the PneumoNP projects.

PathoFinder will have a company booth. They will display next generation multiplex PCR diagnostics kits for infectious diseases. One is under development in the framework of the PneumoNP project.

On Sunday 23rd, Alessandro Pini, from the company SetLance, will give a presentation during the session: Host-pathogen interactions provide opportunities for novel therapy. The session takes place in hall H from 11:30 to 12:30. His presentation will covers “the peptide SET-M33 as novel agent to neutralize and remove LPS in patients with sepsis”.

Meet us also during the session: New drugs against Gram-negatives. The session takes place in hall K on Monday 24th from 09:00 to 11:00. Chiara Falciani, from the company SetLance, will give a presentation entitled “An antimicrobial peptide to face multidrug-resistance emergency: synergies and mechanism of action underpinning efficacy”.

Find all the necessary information related to the event on: www.eccmid.org. The full programme is available on the website ECCMIDLive.

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New publication: Immunomodulatory activity of a novel antimicrobial candidate

Immunomodulatory and anti-inflammatory activity in vitro and in vivo of a novel antimicrobial candidate

Abstract

The synthetic antimicrobial peptide SET-M33 has strong activity against bacterial infections due to Gram-negative bacteria. It is currently in preclinical development as a new drug to treat lung infections caused by Gram-negative bacteria. Here we report its strong anti-inflammatory activity in terms of reduced expression of a number of cytokines, enzymes and signal transduction factors involved in inflammation triggered by lipopolysaccharides (LPS) from P. aeruginosa, K. pneumoniae and E. coli. Sixteen cytokines and other major agents involved in inflammation were analyzed in macrophages and bronchial cells after stimulation with LPS and incubation with SET-M33. The bronchial cells were obtained from a cystic fibrosis patient. A number of these proteins showed up to 100% reduction in expression as measured by RT-PCR, western blot or Luminex technology. LPS neutralization was also demonstrated in vivo by challenging bronchoalveolar lavage of SET-M33-treated mice with LPS which led to a sharp reduction in TNF-α with respect to non SET-M33-treated animals. We also describe strong activity of SET-M33 in stimulating cell migration of keratinocytes in wound healing experiments in vitro, demonstrating powerful immunomodulatory action generally characteristic of molecules taking part in innate immunity.

Authors:

Jlenia Brunetti, Giulia Roscia, Ilaria Lampronti, Roberto Gambari, Leila Quercini, Chiara Falciani, Luisa Bracci and Alessandro Pini

Source:

Brunetti, J. et al. Immunomodulatory and anti-inflammatory activity in vitro and in vivo of a novel antimicrobial candidate. Journal of Biological Chemistry; doi: 10.1074/jbc.M116.750257 (2016).

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M33, the new option to fight severe pneumonia

The antimicrobial peptide M33 may be the long-sought substitute to treat difficult lung infections, like multi-drug resistant pneumonia.

In 2013, the European Respiratory Society predicted 3 millions cases of pneumonia in Europe every year[1]. The standard treatment for pneumonia is an intravenous administration of a combination of drugs. This leads to the development of antibiotic resistance in the population. Gradually, doctors are running out of solutions to cure patients. An Italian company suggests a new option: the M33 peptide.

Few years ago, the Italian company SetLance SRL decided to investigate the M33 peptide. The antimicrobial peptide is an optimized version of an artificial peptide sequence selected for its efficacy and stability. So far, it showed encouraging in-vitro results against multidrug-resistant Gram-negative bacteria, including Klebsiella Pneumoniae. With the support of EU funding to the PneumoNP project, SetLance SRL had the opportunity to develop a new formulation of M33 that enhances its antimicrobial activity.

Action of a M33 peptide on the membrane of a gram-negative bacteria

Fig. Action of a M33 peptide on the membrane of a gram-negative bacteria

 

The new formulation of M33 fights Gram-negative bacteria in three steps. First of all, the M33 binds with the lipopolysaccharides (LPS) on the outer membrane of bacteria. Then, the molecule forms a helix and finally disrupts the membrane provoking cytoplasm leaking. The peptide enabled up to 80% of mice to survive Pseudomonas Aeruginosa-based lung infections. Beyond these encouraging results, toxicity to the new M33 formulation seems to be much lower than antimicrobial peptides currently used in clinical practice like colistin[2].

Lately, SetLance scaled-up the synthesis route and is now able to produce several hundred milligrams per batch. The molecule is robust enough for industrial production. We may expect this drug to go on clinical development and validation at the beginning of 2018.

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[1] http://www.erswhitebook.org/chapters/acute-lower-respiratory-infections/pneumonia/

[2] Ceccherini et al., Antimicrobial activity of levofloxacin-M33 peptide conjugation or combination, Chem Med Comm. 2016;
Brunetti et al., In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Scientific Reports 2016

 

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New publication: In vitro and in vivo tests for a novel antibacterial drug candidate

In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate

Abstract:

A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60–80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years.

In vivo antibacterial activity of SET-M33L peptide in skin infection. Example of images of five animals at day 2.

In vivo antibacterial activity of SET-M33L peptide in skin infection. Example of images of five animals at
day 2.

Authors:

Jlenia Brunetti, Chiara Falciani, Giulia Roscia, Simona Pollini, Stefano Bindi, Silvia Scali, Unai Cossio Arrieta, Vanessa Gómez-Vallejo, Leila Quercini, Elisa Ibba, Marco Prato, Gian Maria Rossolini, Jordi Llop, Luisa Bracci, Alessandro Pini

Source:

Brunetti, J. et al. In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Sci. Rep. 6, 26077; doi: 10.1038/srep26077 (2016).

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New publication: Antimicrobial activity of M33

Antimicrobial activity of levofloxacin – M33 peptide conjugation or combination

Abstract:

M33 is a branched peptide currently under preclinical characterization for development as a new drug against Gram-negative bacteria. Here we report its antibacterial activity in conjugation or combination with levofloxacin (LVFX), a fluoroquinolone antibiotic. Antibacterial assays showed no significant differences in activity when used in conjugation, while the combination of M33 and LVFX showed improved activity against Gram-negative bacteria. Combination treatment therefore opposes antimicrobial-resistance, restoring the effect of LVFX.

M33

Authors:

Federica Ceccherini (SetLance srl), Chiara Falciani (SetLance srl), Martina Onori (SetLance srl),  Silvia Scali (University of Siena), Simona Pollini (University of Siena), Gian Maria Rossolini (University of Siena, University of Florence, Florence Careggi University Hospital), Luisa Bracci (University of Siena, Siena University Hospital) and   Alessandro Pini (University of Siena, Siena University Hospital)

Source:

Med. Chem. Commun., 2016, Advance Article, DOI: 10.1039/C5MD00392J

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