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CORDIS

Modular Design of Bacterial Lipid Mimics for Next-Generation Antimicrobials

Project description

The next generation of antimicrobial drugs

Antimicrobial resistance is a growing health concern hampering the effectiveness of existing antibiotics. The emergence of drug-resistant pathogenic bacteria demands the development of novel antimicrobial solutions. To address this, the EU-funded AmCaLiStat project will develop drugs that target Lipid A, the component that anchors LPS to Gram-negative bacterial membranes. The idea is to disrupt lipid assemblies paramount for membrane integrity and pathogen survival. Using specialised statistical software, scientists will uncover correlations between the structure and activity of drugs against Lipid A, leading to the modular synthetic design of promising new antimicrobials. Apart from novel drugs, this approach could potentiate obsolete antimicrobials.

Objective

"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."

Keywords

Coordinator

UNIVERSITAET GRAZ
Net EU contribution
€ 174 167,04
Address
UNIVERSITATSPLATZ 3
8010 Graz
Austria

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Region
Südösterreich Steiermark Graz
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 174 167,04