The threat of multi-drug resistant bacteria as bioterrorism agents, but also the increasing drug resistance of pathogens in a hospital setting, poses a serious and potentially devastating medical problem that requires conceptually new treatment modalities using novel antibiotics. To meet this need, we propose an applied research program that aims to develop and experimentally validate an integrated antimicrobial drug discovery scheme. In particular, as metabolic activity is a key integrator of all prokaryotic functions, through the analysis of their system-level metabolic organization we will identify those bacterial enzymes whose activity, alone or in combination, is required at all times for the viability of three Category A bacterial bioterrorism agents and two important pathogenic bacteria with significant problem of multidrug resistance in the hospital setting. We will then identify and experimentally validate a series of small-molecule inhibitors against these enzyme targets, which can subsequently serve as structural leads for the development of new antibiotics. The proposed project will be carried out in a framework of a well-established, tightly integrated multidisciplinary effort among research groups of a molecular biologist and physician-scientist with experience in the theoretical and experimental analysis of bacterial metabolic networks (Z. N. Oltvai), a theoretical physicist with experience in assessing the structural and dynamical features of complex networks (A.-L. Barabasi), a biotechnology company with extensive experience with genome annotation, metabolic reconstruction and corresponding wet lab confirmation (Integrated Genomics, Inc.), and an organic and computational chemist with extensive experience in computational drug design and development (O. Wiest). The project will be further aided by the active computational and experimental support of four Consultants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI070499-05
Application #
7876892
Study Section
Special Emphasis Panel (ZAI1-LR-M (M2))
Program Officer
Xu, Zuoyu
Project Start
2006-07-15
Project End
2011-12-30
Budget Start
2010-07-01
Budget End
2011-12-30
Support Year
5
Fiscal Year
2010
Total Cost
$548,309
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ahn, Yong-Yeol; Lee, Deok-Sun; Burd, Henry et al. (2014) Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents. PLoS One 9:e85195
Isin, Basak; Tirupula, Kalyan C; Oltvai, Zoltán N et al. (2012) Identification of motions in membrane proteins by elastic network models and their experimental validation. Methods Mol Biol 914:285-317
Vazquez, Alexei; Oltvai, Zoltan N (2011) Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology. PLoS One 6:e19538
Vazquez, Alexei; Markert, Elke K; Oltvai, Zoltan N (2011) Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS One 6:e25881
Vazquez, Alexei; Liu, Jiangxia; Zhou, Yi et al. (2010) Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol 4:58
Henriksen, S T; Liu, J; Estiu, G et al. (2010) Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays. Bioorg Med Chem 18:5148-56
Lee, Deok-Sun; Burd, Henry; Liu, Jiangxia et al. (2009) Comparative genome-scale metabolic reconstruction and flux balance analysis of multiple Staphylococcus aureus genomes identify novel antimicrobial drug targets. J Bacteriol 191:4015-24
Venkatesan, Kavitha; Rual, Jean-François; Vazquez, Alexei et al. (2009) An empirical framework for binary interactome mapping. Nat Methods 6:83-90
Park, Juyong; Lee, Deok-Sun; Christakis, Nicholas A et al. (2009) The impact of cellular networks on disease comorbidity. Mol Syst Biol 5:262
Adams, James Corey; Keiser, Michael J; Basuino, Li et al. (2009) A mapping of drug space from the viewpoint of small molecule metabolism. PLoS Comput Biol 5:e1000474

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