Project

Outline of Aeropath
The Project

Outline of AEROPATH

AEROPATH is an ambitious multidisciplinary research programme designed to support early stage antimicrobial drug development. We will advance understanding, at the molecular level, of fundamental and important aspects of the biology of Gram-negative bacteria targeting in particular the important pathogen Pseudomonas aeruginosa. Our title is derived from P. aeruginosa pathogenesis.

Gram-negative bacteria present a particular problem in Europe. An aging population, improved treatments for long-term human diseases such as diabetes and cancers, inappropriate prescription practices and a significant increase in the number of immunocompromised individuals all contribute to a larger population who are highly susceptible to bacterial infection and to a frightening increase in both infection rates and drug resistance. This, together with the lack of new drugs being developed creates an urgent need for the appropriate molecular sciences research that underpins the difficult and longer-term studies required to develop antibiotics.

We will exploit modern technologies in chemo-bioinformatics, proteomics, molecular and structural biology, computational chemistry and screening technologies to identify ligands and inhibitors (hit and lead compounds) with the potential to drive the discovery of improved therapies for Gram-negative infections. The research covers six work packages and these are outlined below. The outcome will be the identification of small organic molecules with the potential to directly influence medicinal chemistry programmes of drug development.

The Project

The research involves eight integrated work packages.

(WP-1) in vivo target assessment

Leader: Lionex GmbH
The Work Package will involve experimental validation and identification of novel drug targets by gene knockout in P. aeruginosa.

(WP-2) Characterisation of novel targets

Leader: University of St. Andrews
This Work Package will involve cloning, biochemical and structural characterisation of the targets.

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(WP-3) in silico target analysis

Leader: Dundee University
This Work Package will involve a genome-wide bio-chemoinformatics analysis to assess druggability of targets to guide the next stages and also feedback to WP-1.

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(WP-4) Hit discovery using structure-based methods

Leader: Karolinska Institutet
This Work Package will involve a directed search for ligands/inhibitors, exploiting data from WP-1 and WP-2 with decision making influenced by WP-3, for these validated antimicrobial drug targets by virtual screening (VS), and fragment screening (FS).

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(WP-5) Hit discovery by HTS

Leader: Dundee University
This Work Package will involve High-throughput screening (HTS) campaigns on a carefully prioritised subset of targets.

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(WP-6) Characterisation of target-ligand complexes

Leader: Dundee University
This Work Package will involve the characterisation of interactions between the targets and ligands/inhibitors by biochemical and crystallographic study, computational modeling, design and further modeling to enhance binding properties and derive structure activity relationships.

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(WP-7) Management

Leader: Dundee University

The objective of this Work Package is to supervise the overall activities of the project. This involves co-ordination of the individual partner’s activities, interactions with similar projects, interaction with the European Commission and all other general project management responsibilities required for a successful project. All partners are involved in this Work Package.

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(WP-8) Dissemination

Leader: Dundee University

The objective of this Work Package is to disseminate the research outputs of the project. This includes

• Guiding the research activity towards finding industry relevant solutions and providing objective and quantifiable targets to inform research goals
• developing strategic plans for exploitation of the intellectual and technological results of the project
• actively promoting research results to the general public
• spreading awareness of the knowledge gained between the project partners and the wider scientific and industrial communities

All partners are involved in this Work Package.

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