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Modular Design of Bacterial Lipid Mimics for Next-Generation Antimicrobials

Descripción del proyecto

La próxima generación de fármacos antimicrobianos

La resistencia antimicrobiana constituye un problema de salud creciente y dificulta la eficacia de los antibióticos existentes. La nueva aparición de bacterias patógenas farmacorresistentes requiere el desarrollo de nuevas soluciones antimicrobianas. Para abordar este problema, el proyecto financiado con fondos europeos AmCaLiStat desarrollará fármacos que se centren en el lípido A, el componente que fija los lipopolisacáridos (LPS) a las membranas de las bacterias gramnegativas. La idea del proyecto consiste en alterar los ensamblajes de los lípidos que son fundamentales para la integridad de la membrana y la supervivencia de los patógenos. Mediante el uso de un «software» estadístico, los científicos del proyecto revelarán las correlaciones entre la estructura y la actividad de los fármacos contra el lípido A, lo cual llevará al diseño sintético modular de unos nuevos antimicrobianos prometedores. Aparte de los nuevos fármacos, este método podría potenciar el uso de antimicrobianos obsoletos.

Objetivo

"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."

Palabras clave

Coordinador

UNIVERSITAET GRAZ
Aportación neta de la UEn
€ 174 167,04
Dirección
UNIVERSITATSPLATZ 3
8010 Graz
Austria

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Región
Südösterreich Steiermark Graz
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 174 167,04