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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: protein structure; Gram-negative bacteria; Pseudomonas aeruginosa; infectious diseases; structure-based inhibitor design
Diamond Keywords: Bacteria
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I02-Macromolecular Crystallography
,
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Other Facilities: I911-2, I911-3 at MAX IV; ID23-1, ID14-1, ID14-4, ID29, BM14 at ESRF
Added On:
07/01/2013 10:18
Documents:
wd5195.pdf
Discipline Tags:
Pathogens
Antibiotic Resistance
Infectious Diseases
Health & Wellbeing
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)