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BITS2007 Meeting
BITS2007 Meeting



26-28 April 2007 Napoli, Italy

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Critical points in a pathogen bacterial network and their implication for drug discovery.
 
Motivation
Complex systems such as living cells have a `robust yet fragile` feature, in which
robustness in response to certain perturbation is inevitably associated with
fragility in response to other perturbations (Kitano, Nat Rev Drug Discov., 2007).
Finding the points of fragility of the pathogenic microbial cells is a key issue in
antibacterial drug discovery. Here we describe a general approach to identify control
points in a microbial molecular network, which could be targets for novel drugs. The
strategy is implemented on  Helicobacter pylori 26695, an human gastric pathogen
infecting almost half of the world population (Beswick et al., World J
Gastroenterol., 2006). The entire metabolic network of the pathogen is screened to
find biochemically critical points, e.g. enzymes which uniquely consume and/or
produce a certain metabolite (Rahman and Schomburg, Bioinformatics, 2006). A
comparative study between the identified  bacterial critical points and the known
essential genes for H.pylori was performed. Enzymes acting as critical points in the
human biochemical network as well as in the pathogen network were removed. Further
selections were made on results obtained by performing a homology search against the
human genome. Finally, the essentiality of the identified targets is cross-validated
by in silico deletion studies on a recent genome-scale metabolic model of H.pylori.

Methods
We consider a reconstructed metabolic network (enzymes/metabolites) of Helicobacter
Pylori 26695, built using the LIGAND (Goto et al, Nucleic Acids Res., 2002) database
from KEGG (Kanehisa et al., Nucleic Acids Res., 2004) and the BRENDA enzyme database
(Schomburg et al., Nucleic Acids Res., 2004). We used the Pathway Hunter algorithm
(Rahman et al., Bioinformatics,  2005) to estimate and rank the bio-chemically
critical points in the network. A database of essential genes was built using data
from single knockout experiments and from global transposon mutagenesis (Salama et
al., J. Bacteriol., 2004; Baldwin et al., J. Bacteriol., 2006). The homology search
between the human and H.pylori enzymes was executed using BLAST and enzymes with a
closest homologue with e-values < 1.0e-02 were removed. In silico deletion studies
were performed  using costraint-based reconstruction and analysis (COBRA tecnique:
Palsson et al., Nat Methods, 2007) on the H.pylori iIT341 GSM/GPR in silico metabolic
model (Thiele et al., J. Bacteriol.,  2005).

Results
The strategy was implemented on the pathogen bacterial network of Helicobacter pylori
strain 26695. Potential drug targets are proposed based on the analysis of the top 20
critical points in the bacterial network. These enzymes are compared to the essential
genes for H. pylori identified from biomedical literature, in order to extract
consensus targets for the bacterium`s survival and pathogenicity. Once identified,
the list of potential targets is filtered in two steps. First, a comparative study
was performed between the human metabolic network and pathogen critical points to
discriminate common critical enzymes. A homology search was then performed against
human genome to find non-homologus potential drug targets from the pathogen critical
points. 
Finally, a simulation of growth phenotypes resulting from single and double deletion
of target enzymes was carried out on a recent genome-scale metabolic reconstruction
of H.pylori, in order to cross-validate the essentiality of selected candidates.
 
Id: 225
Place: Napoli, Italy
Centro Congressi "Federico II"
Via Partenope 36
Napoli
Starting date:
-- not yet scheduled --   
Duration: 01h00'
Contribution type: Poster
Primary Authors: LOGUERCIO, Salvatore (Department of Biological sciences-Biostructures section- University of Naples `Federico II`, Napoli)
Presenters: LOGUERCIO, Salvatore
 
Included in session: Poster Session
Included in track: Gene expression and system biology
 




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