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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

In Search of New Anti-bacterial Target Genes: A Comparative/Structural Genomics Approach

Author(s): Jean-Michel Claverie, Vincent Monchois, Stephane Audic, Olivier Poirot and Chantal Abergel

Volume 5, Issue 7, 2002

Page: [511 - 522] Pages: 12

DOI: 10.2174/1386207023330002

Price: $65

Abstract

We outline a joint academic/industrial (CNRS/AVENTIS) functional genomics project aiming at the discovery of new anti-bacterial gene targets. Starting from all publicly available bacterial genomes, a subset of the most evolutionary conserved protein-coding genes has been identified. We retained genes with clear homolog in E. coli and at least one gram-positive bacterium among B.subtilis, M. tuberculosis, L. lactis or S. pyogenes. This subset was further reduced to genes encoding non-membrane proteins of unknown or hypothetical functions. The 221 E. coli Open Reading Frames (ORFs) identified through this comprehensive bioinformatic analysis are now submitted to a systematic 3-D structure determination protocol including cloning, protein expression and purification, crystallisation and X-ray diffraction. Our strategy was designed to focus on promising wide-spectrum targets as well as original biochemical pathways. Bioinformatics is used throughout all phases of project, including the initial large-scale comparative genomics analyses, the purification/expression and crystallisation stages for the detection of helpful sequence-specific features (e.g. cofactor binding motifs, non-structured N- or C- term extremities, etc … ), and finally for the interpretation of the structures in conjunction with multiple sequence alignments for the identification of key residues, interaction areas on molecular surfaces, and overall function predictions.

Keywords: anti-bacterial, target discovery, structural genomics, bioinformatics


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