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Chemogenomics and orthology-based design of antibiotic combination therapies

Chandrasekaran, Sriram and Çokol Çakmak, Melike and Şahin, Nil and Yılancıoğlu, Kaan and Kazan, Hilal and Collins, James J. and Çokol, Murat (2016) Chemogenomics and orthology-based design of antibiotic combination therapies. Molecular Systems Biology, 12 (5). ISSN 1744-4292

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Official URL: http://dx.doi.org/10.15252/msb.20156777

Abstract

Combination antibiotic therapies are being increasingly used in the clinic to enhance potency and counter drug resistance. However, the large search space of candidate drugs and dosage regimes makes the identification of effective combinations highly challenging. Here, we present a computational approach called INDIGO, which uses chemogenomics data to predict antibiotic combinations that interact synergistically or antagonistically in inhibiting bacterial growth. INDIGO quantifies the influence of individual chemical-genetic interactions on synergy and antagonism and significantly outperforms existing approaches based on experimental evaluation of novel predictions in Escherichia coli. Our analysis revealed a core set of genes and pathways (e.g. central metabolism) that are predictive of antibiotic interactions. By identifying the interactions that are associated with orthologous genes, we successfully estimated drug-interaction outcomes in the bacterial pathogens Mycobacterium tuberculosis and Staphylococcus aureus, using the E. coli INDIGO model. INDIGO thus enables the discovery of effective combination therapies in less-studied pathogens by leveraging chemogenomics data in model organisms.

Item Type:Article
Uncontrolled Keywords:chemogenomics; combination therapy; drug resistance; Mycobacterium tuberculosis; Staphylococcus aureus
Subjects:UNSPECIFIED
ID Code:31308
Deposited By:Melike Çokol Çakmak
Deposited On:05 May 2017 15:13
Last Modified:05 May 2017 15:13

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