Category Archives: Publication

New publication: Experimental methods for aerosol measurements in human airways

Experimental methods for flow and aerosol measurements in human airways and their replicas

Abstract

Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes.

This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated.

Graphical abstract

The review classifies the methods into following categories:

  1. point-wise and planar methods for velocimetry in the airways,
  2. classic methods for the measurement of the regional distribution of inhaled particles,
  3. standard medical imaging methods applicable to the measurement of the regional aerosol distribution and
  4. emerging and nonconventional methods.

All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given.

Authors

Frantisek Lizal, Jan Jedelsky, Kaye Morgan, Katrin Bauer, Jordi Llop, Unai Cossio, Stavros Kassinos, Sylvia Verbanck, Jesús Ruiz-Cabello, Arnoldo Santos, Edmund Koch, Christian Schnabel

Source

Lizal, F., Jedelsky, J., Morgan, K., Bauer, K., Llop, J., Cossio, U., … & Koch, E. (2017). Experimental methods for flow and aerosol measurements in human airways and their replicas. European Journal of Pharmaceutical Sciences.

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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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New publication: Synergistic activity profile of M33 against MDR strains of Gram-negative bacteria

Synergistic activity profile of an antimicrobial peptide against multidrug-resistant and extensively drug-resistant strains of Gram-negative bacterial pathogens

Abstract

Infection sustained by multidrug-resistant and extensively drug-resistant bacterial pathogens is often untreatable with the standard of care antibiotics, and the combination of anti-infective compounds often represents the only therapeutic strategy to face this major clinical treat. SET-M33 is a novel antimicrobial peptide (AMP) that has demonstrated in vitro and in vivo antimicrobial activity against Gram-negative bacteria and has shown interesting features in preclinical evaluation. Particularly, it showed efficacy against a number of multidrug-resistant and extensively drug-resistant clinical strains of Gram-negative pathogens, in in vitro and in vivo assessments.

Visual abstract of M33SET-M33 showed synergistic activity with antibiotics of different families against these clinically relevant strains. A synergistic effect was observed for SET-M33 in combination with rifampin, meropenem, aztreonam, and tobramycin mostly on K. pneumoniae and A. baumannii strains, while the SET-M33 plus ciprofloxacin combination was additive with all tested strains. Synergy was not apparently linked to the bacterial species or phenotype but was rather strain-specific, highlighting the need for individual strain testing for synergistic antimicrobial combinations.

These findings extend current knowledge on synergistic activity of AMPs in combination with conventional agents and support the potential role of SET-M33 as a novel therapeutic agent against antibiotic-resistant Gram-negative pathogens.

Authors

Simona Pollini, Jlenia Brunetti, Samanta Sennati, Gian Maria Rossolini, Luisa Bracci, Alessandro Pini, Chiara Falciani

Source

S. Pollini et al. (2017). Synergistic activity profile of an antimicrobial peptide against multidrug-resistant and extensively drug-resistant strains of Gram-negative bacterial pathogens. Journal of Peptide Science.

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New publication: Synthesis of Single–Chain Nanoparticles in Aqueous Media

Synthesis and Functionalization of Dextran–Based Single–Chain Nanoparticles in Aqueous Media

Abstracts

Water-dispersible dextran-based single-chain polymer nanoparticles (SCPNs) were prepared in aqueous media and mild conditions. Radiolabeling of the resulting biocompatible materials allowed the study of lung deposition of aqueous aerosols after intratracheal nebulization by means of single-photon emission computed tomography (SPECT), demonstrating their potential use as imaging contrast agents.

Authors

Raquel Gracia, Marco Marradi, Unai Cossío, Ana Belen Benito, Adrián Pérez-San Vicente, Vanessa Gómez-Vallejo, Hans J Grande, Jordi Llop and Iraida Loinaz

Sources

Gracia R et al. Synthesis and Functionalization of Dextran–Based Single–Chain Nanoparticles in Aqueous Media. J. Mater. Chem. B, 2017. DOI: 10.1039/C6TB02773C.

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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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New publication: in vitro testing platform for aerosols

Development of an in vitro testing platform for aerosols containing inhalable antiobiotically active compounds as a part of the EU-project “PneumoNP”

This article belongs to a special issue gathering abstracts of the 52nd Congress of the European Societies of Toxicology (EUROTOX). This event was held in Seville, Spain, from 4th to 7th September 2016.

Authors:

D. Ritter (Department of In vitro and Mechanistic Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany), J. Knebel (Department of In vitro and Mechanistic Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany), S. Wronski (Department of In vitro and Mechanistic Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany), A. Montes (Ingeniatrics Tecnologias, S.L., Sevilla, Spain), M. Niehof (Department of In vitro and Mechanistic Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany)

Source:

Toxicology Letters 258:S146 · September 2016

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New publication: Models of in-vivo Bacterial Infections

Models of in-vivo Bacterial Infections for the Development of antimicrobial Peptide-Based Drugs

The increasing frequency of multi-resistant Gram-positive and Gram-negative bacteria and a long-term decreasing trend in the development of new antimicrobial molecules prompts research for new anti-infective agents with new modes of action. Antimicrobial peptides (AMPs) are considered an interesting class of antibacterial molecules. Many new AMPs have been discovered and some are being evaluated for the development of new antibacterial therapeutics. Since the development of new antibacterial drugs has been neglected for decades, we are now facing with extreme medical need combined with a lack of technical experimental progress in setting up efficient models of antibacterial activity in animals. Here we review experiments with AMPs in animal models of sepsis, pneumonia and skin infection caused by bacteria. Animal models of infection have been of enormous predictive value in antibacterial drug discovery, both for elucidating AMP efficacy in the treatment of experimentally induced infection and for comparing the effectiveness of two or more antibiotics.

Authors:

Brunetti J, Falciani C (Setlance srl), Bracci L, Pini A.

Source:

Curr Top Med Chem. 2016 Jul 13.

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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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