1,721,173 research outputs found
ROLE OF THE BACTERIAL CELL WALL GLYCO-CONJUGATES IN ELICITATION OR SUPRESSION OF EUKARYOTIC INNATE IMMUNITY
No full textNuclear Magnetic Resonance spectroscopy studies of proteins-glycoconjugates interactions
No full text“Naturally occurring antimicrobials to counteract lung infections in cystic fibrosis patients: cecropin A-melittin (CA-M) hybrid peptides and polymixins”
No full textBackground: The management of cystic fibrosis (CF) infections by Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc) is significantly affected by the emergence of multidrug-resistant (MDR) strains. New therapeutic strategies are needed to circumvent these problems. Naturally occurring antimicrobials, such as antimicrobial peptides (AMPs), are being sought as “lead compound” for developing alternative antimicrobials. The design of enhanced synthetic variants to be used alone or in combination with other antibiotics could, therefore, represent an alternative strategy to counteract multidrug-resistant (MDR) strains.
Hypothesis and objectives: The present project will be focused on the definition of novel therapeutic strategies in the treatment of CF lung infections based on the use of naturally occurring AMPs: Cecropin A-Melittin (CA-M) hybrid peptides and their derivates (CA-M hybrids), as well as polymixins. We aim to: i) explore the mechanisms of interaction of CA-M hybrids with bacterial cell envelope, in order to define the molecular requisites for resistance, adaptation and modulation of the host immune response by opportunistic CF pathogens such as P. aeruginosa and Bcc; and ii) evaluate the in vivo and in vitro activity of CA-M hybrids, alone and in combination with antibiotics commonly used in CF therapy (i.e., tobramycin), against planktonic and biofilm cells of CF MDR P. aeruginosa and Bcc strains.
Material, methods: production of CA-M derivatives via synthetic methodologies; elucidation of the primary structure of bacterial lipopolysaccharide (LPS) via chemical, spectroscopic and spectrometric techniques; assessment of the pro-inflammatory activities of such isolates; characterization of the micro- and mesostructuring of lipopolysaccharide in lipid bilayers and study of the interaction of LPS-based bilayers with CA-M hybrids; Evaluation, in “CF-like” conditions, of CA-M hybrids activity against planktonic and biofilm phenotype of P. aeruginosa and Bcc; Assessment of toxicity of selected CA-M hybrids and protective effect in murine models of pulmonary acute and chronic infection including CF mice.
Expected results and spin-offs: Elucidation of mechanisms of bacterial interaction with AMP (as CA-M hybrids) and definition of molecular requisite for resistance, adaptation and modulation of the host immune response. Characterization of the primary and supramolecular structure of LPS and of its interaction with CA-M hybrids; assessment of AMP in vitro and in vivo antimicrobial activity of CA-M hybrids and derivatives: evaluation of the antibacterial potential of CA-M hybrids, alone and in combination with antibiotics
In vitro and in vivo studies of novel antimicrobials targeting bacterial cytoskeleton and cell surface virulence markers in the treatment of Burkholderia cepacia complex infection
No full textThe Burkholderia cepacia complex (Bcc) comprises opportunistic pathogens in CF patients whose unifying theme is the high level of antibiotic resistance. Lung transplantation is the only treatment that improves both the quantity and quality of life of CF patients with advanced lung disease. It has been shown that Bcc infections are the second most common infection in CF prior to transplantation. A dramatic drawback of Bcc infections is that they limit the selection of CF patients for lung transplantation because of the high risk of post-operative death; poor outcomes are common in those patients with pre-operative B. cenocepacia infection. New antimicrobial compounds with activity against the Bcc are needed. The bacterial cytoskeleton has emerged as a new target for antimicrobials. We hypothesize the bacterial cytoskeleton plays a central role in the assembly and organization of macromolecular protein complexes including those important in pathogenicity. The cytoskeleton inhibitors alter the bacterial membrane, comprising virulence factors involved in pathways controlling inflammation and host defences as lipopolysaccharides. The comprehension of such induced modifications can contribute to understand how bacteria adapt and respond to antimicrobial compounds, which are the secondary alterations induced by cytoskeleton inhibitors and their effect on bacterial viability and virulence. In this frame, to set up new antibacterial therapies, this project is aimed to: the elucidation of the in vitro and in vivo antimicrobial activity of such bacterial cytoskeleton inhibitors on clinically derived Bcc strains from patients undergoing lung transplantation with Bcc infections; analysis of secondary effects of these cytoskeleton inhibitors on bacterial membrane including changes in Lipopolysaccharide composition, structure and biological activity; assessment of the in vivo antimicrobial activity and host toxicity of novel cytoskeleton inhibitors in the murine model of acute and chronic infection
Study on interactions between new derivatives of nucleosides and biologicaly valuable glycosyltransferases by STD
No full textLe chitina sintasi, enzimi coinvolyi nell’ultimo step della formazione della parete cellulare fungina, sono tra le più iomportanti glicosiltransferasi, perché onnipresenti e indispensabili alla loro sopravvivenza fungina. La loro assenza nei mammiferi rende le chitina sintasi un target ideale per lo sviluppi di nuovi farmaci. In questo contesto si inserisce la presente proposta di cooperazione Italia-Polonia, che sarà incentrata sullo studio delle interazioni tra nuovi derivati nucleosidici, sintetizzati dalla gruppo della prof. Wandzik, e le chitina sintasi mediante l’utilizzo di tecniche avanzate di spettroscopia NMR (in particolare STD NMR), eseguite dal gruppo della Dott. Silipo, che permetteranno di rilevare esclusivamente i ligandi aventi affinità di legame verso le biomolecole in esame e di studiarne le modalità di interazione. A partire dalla comprensione del meccanismo d'azione e l'identificazione di gruppi funzionali responsabili del riconoscimento e dell’interazione con la proteina l’ analisi STD NMR, eseguite dal gruppo della dott. Silipo ci permetterà di identificare le regioni del substrato che sono fondamentali per il riconoscimento molecolare e possono quindi essere utilizzati come potenziali epitopi vaccinali o per sviluppare inibitori enzimatici.
La collaborazione tra i due gruppi sarà quindi fondamentale per lo screening di librerie composti sintetizzati dal gruppo di ricerca polacco della prof. Wandzik e testati nella loro abilità di interagire con la chitina sintasi dal gruppo di ricerca italiano diretto dalla dott.ssa Silipo
Structure and bioactivity of bacterial glycolipids as targets for biomedical applications
No full textStucture of macromolecules from Gram-negative bacteriainvolved in elicitation of plant immune system
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