The AEROPATH project targeting Pseudomonas aeruginosa: crystallographic studies for assessment of potential targets in early-stage drug discovery

DOI: 10.1107/S1744309112044739
PMID: 23295481

Authors: Lucile Moynie (University of St Andrews) , Robert Schnell (Karolinska Institutet) , Stephen A. Mcmahon (University of St Andrews) , Tatyana Sandalova (Karolinska Institutet) , Wassila Abdelli Boulkerou (University of St Andrews) , Jason W. Schmidberger (Karolinska Institutet) , Magnus Alphey (University of St Andrews) , Cyprian Cukier (Karolinska Institutet) , Fraser Duthie (University of St Andrews) , Jolanta Kopec (Karolinska Institutet) , Huanting Liu (University of St Andrews) , Agata Jacewicz (Karolinska Institutet) , William N. Hunter (University of Dundee) , James H. Naismith (Center for Biomolecular Sciences, University of St. Andrews) , Gunter Schneider (Karolinska Institutet)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section F Structural Biology And Crystallization Communications , VOL 69 , PAGES 25 - 34

State: Published (Approved)
Published: January 2013

Abstract: Bacterial infections are increasingly difficult to treat owing to the spread of antibiotic resistance. A major concern is Gram-negative bacteria, for which the discovery of new antimicrobial drugs has been particularly scarce. In an effort to accelerate early steps in drug discovery, the EU-funded AEROPATH project aims to identify novel targets in the opportunistic pathogen Pseudomonas aeruginosa by applying a multidisciplinary approach encompassing target validation, structural characterization, assay development and hit identification from small-molecule libraries. Here, the strategies used for target selection are described and progress in protein production and structure analysis is reported. Of the 102 selected targets, 84 could be produced in soluble form and the de novo structures of 39 proteins have been determined. The crystal structures of eight of these targets, ranging from hypothetical unknown proteins to metabolic enzymes from different functional classes (PA1645, PA1648, PA2169, PA3770, PA4098, PA4485, PA4992 and PA5259), are reported here. The structural information is expected to provide a firm basis for the improvement of hit compounds identified from fragment-based and high-throughput screening campaigns.

Journal Keywords: Bacterial; Base; Catalytic; Crystallography; X-Ray; Drug; Escherichia; Models; Molecular; Protein; Pseudomonas aeruginosa

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: MAX IV, ESRF