Target-Pathogen


NAR Molecular Biology Database Collection entry number 63
Fernandez Do Porto, Dario; Sosa, Ezequiel; Burguener, Germán; Lanzarotti, Esteban; Defelipe, Lucas A; Radusky, Leandro; Pardo, Agustín; Martí, Marcelo; Turjanski, Adrián
1 Plataforma de Bioinformática Argentina (BIA), Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina
2 IQUIBICEN-CONICET, Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina
3 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, C1428EHA Ciudad de Buenos Aires, Argentina

Database Description

The successful use of antibiotics has been facing challenges because microbial pathogens are developing various forms of resistance in the last decades (1). Despite this critical situation, new drug development projects have been inadequate for reasons ranging from bad selection of targets to reduced antimicrobial drug discovery efforts by pharmaceutical companies (2, 3). Currently, it is accepted that identification and validation of appropriate targets are critical steps for designing new drugs. In this sense, Next Generation Sequencing is increasingly aiding the evaluation of gene function, essentiality and suitability for drug development. Nevertheless there is a lack of online resources that allows genome wide based data consolidation from diverse sources in order to define a list of potential targets. Here, we present Target-Pathogen database (target.sbg.qb.fcen.uba.ar/patho), an online resource that allows genome wide based target ranking and identification. By integrating and weighting the data, focusing on essentiality, metabolic role and structural druggability prediction of proteins, Target-Pathogen facilitates the identification and prioritization of candidate targets suitable for new drug development projects.
Available genomic data for pathogens has created new opportunities for drug discovery and development to fight them, including new resistant and multiresistant strains. In particular structural data must be integrated with both, gene information and experimental results. In this sense, there is a lack of an online resource that allows genome wide based data consolidation from diverse sources together with thorough bioinformatic analysis that allows easy filtering and scoring for fast target selection for drug discovery. Here, we present Target-Pathogen database (http://target.sbg.qb.fcen.uba.ar/patho), designed and developed as an online resource that allows the integration and weighting of protein information such as: function, metabolic role, off-targeting, structural properties including druggability, essentiality, and omic experiments, to facilitate the identification and prioritization of candidate drug targets in pathogens. We include in the database ten genomes of some of the most relevant microorganisms for human health (Mycobacterium tuberculosis, Mycobacterium leprae, Klebsiella pneumoniae, Plasmodium vivax, Toxoplasma gondii, Leishmania major, Wolbachia bancrofti, Trypanosoma brucei, Shigella dysenteriae and Schistosoma Smanosoni) and show its applicability. New genomes can be uploaded upon request.
Target-Pathogen is an easy-to-use web-based platform which allows genome wide based data consolidation from diverse sources in a user-friendly manner , with graphical interface for structural visualization and manipulation. With structurome and drugome information Target-Pathogen is a unique resource to analyze whole genomes of relevant pathogens. Using Target-Pathogen, researchers can quickly prioritize genes of interest in a fast and intuitive manner, running simple queries (such as looking for proteins with high druggability score or associated with choke-points reactions), filtering by different data, assigning numerical weights for different properties and combining these results to produce a ranked list of targets. In this sense, an aspect that distinguishes Target- Pathogen is that it permits users to upload their own data. Once the data is uploaded, it can be included to obtain a personalized ranking of candidate drug targets in pathogens. Another key feature where Target-Pathogen stands alone is its ability to rank not only proteins but entire pathways. This characteristic allows prioritizing promising pathways to develop new drugs in order to synergistically attack several proteins of the same pathway. We have now selected ten relevant genomes but the database can be easily updated with other relevant pathogens as the bioinformatic pipelines have been automatized. In this sense, we will extend Target-Pathogen to more organisms than the current version, that's why we also encourages users to request new genomes of interest and join our team by mailing to target@biargentina.com.ar.
The goal of Target-Pathogen is not to replace wet strategies for target identification. Rather, our goal is to become a useful resource for researchers working in the field of target identification and/or drug discovery to translate biological questions in a computational tractable way by exploring, filtering and weighting the vast quantity of genome-scale data sets. Target-Pathogen will be continuously updated as part of a national initiative to develop tools for pathogens.

References

References 1. Martens,E. and Demain,A.L. (2017) The antibiotic resistance crisis, with a focus on the United States. J. Antibiot. , 70, 520–526.
2. Fernandes,P. (2015) The global challenge of new classes of antibacterial agents: an industry perspective. Curr. Opin. Pharmacol., 24, 7–11.
3. Wenzel,R.P. (2004) The Antibiotic Pipeline — Challenges, Costs, and Values. N. Engl. J. Med., 351, 523–526.

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