Description du projet
La prochaine génération de médicaments antimicrobiens
La résistance aux antimicrobiens constitue un problème de santé croissant qui entrave l’efficacité des antibiotiques actuels. L’apparition de bactéries pathogènes résistantes aux médicaments exige le développement de nouvelles solutions antimicrobiennes. Pour y remédier, le projet AmCaLiStat, financé par l’UE, mettra au point des médicaments qui ciblent le lipide A, un composant qui ancre des lipopolysaccharides aux membranes des bactéries à Gram négatif. L’idée consiste à déstabiliser les assemblages lipidiques qui sont essentiels à l’intégrité membranaire et à la survie de l’agent pathogène. En utilisant un logiciel statistique spécialisé, les scientifiques dévoileront les corrélations entre la structure et l’activité des médicaments contre le lipide A, en aboutissant à la conception synthétique modulaire de nouveaux antimicrobiens prometteurs. En plus de nouveaux médicaments, cette approche pourrait potentialiser des antimicrobiens obsolètes.
Objectif
"Antimicrobial resistance in bacteria is a growing public health crisis, as common drugs are becoming ineffective against many species of pathogenic bacteria. This research aims to devise highly specific and stable antimicrobials, which target the amphiphilic component that anchors LPS to Gram-negative bacterial membranes, “Lipid A”, for direct antimicrobial effect and to potentiate other antimicrobials. Taking inspiration from bacterial lipids, which possess multiple tails and a polybasic headgroup, synthetic cationic lipidoids have the potential to be highly specific bacterial membrane-targeting antimicrobials. Preliminary results demonstrate that some cationic lipidoids bind and disrupt bacterial lipid assemblies, and significantly inhibit the growth of E. coli at micromolar concentrations. However, the breadth of potential molecular structures arising from the range of available starting materials makes the search for optimum compounds an insurmountable task. This proposal outlines an innovative use of statistical software to steer modular synthetic design and expedite the identification of promising new antimicrobials. Relative to a ""one-factor-at-a-time"" approach, statistical design can quickly uncover correlations between structure and activity, and unexpected interactions between structural variables, thus accelerating the discovery of antimicrobial compounds that would not otherwise be obvious. In addition to uncovering new compounds selective to bacteria, libraries of lipidoids will be investigated to help uncover design rules for the effect of shape on membrane interactions, and generic mechanisms of membrane-targeting antimicrobial action. Results could also lead to new means to potentiate obsolete antimicrobials that are impermeable to bacterial membranes, or act as a chaperone for highly effective but relatively unstable antimicrobial peptides."
Champ scientifique
- natural sciencescomputer and information sciencessoftware
- medical and health scienceshealth sciencespublic health
- natural sciencesbiological sciencesmicrobiologybacteriology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
8010 Graz
Autriche