Abstract
BackgroundIn spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year. This is mainly due to the emergence of drug-resistance varieties of TB. The current treatment strategies for the drug-resistance TB are of longer duration, more expensive and have side effects. This highlights the importance of identification and prioritization of targets for new drugs. This study has been carried out to prioritize potential drug targets of Mycobacteriumtuberculosis H37Rv based on their flow to resistance genes.MethodsThe weighted proteome interaction network of the pathogen was constructed using a dataset from STRING database. Only a subset of the dataset with interactions that have a combined score value ≥770 was considered. Maximum flow approach has been used to prioritize potential drug targets. The potential drug targets were obtained through comparative genome and network centrality analysis. The curated set of resistance genes was retrieved from literatures. Detail literature review and additional assessment of the method were also carried out for validation.ResultsA list of 537 proteins which are essential to the pathogen and non-homologous with human was obtained from the comparative genome analysis. Through network centrality measures, 131 of them were found within the close neighborhood of the centre of gravity of the proteome network. These proteins were further prioritized based on their maximum flow value to resistance genes and they are proposed as reliable drug targets of the pathogen. Proteins which interact with the host were also identified in order to understand the infection mechanism.ConclusionPotential drug targets of Mycobacteriumtuberculosis H37Rv were successfully prioritized based on their flow to resistance genes of existing drugs which is believed to increase the druggability of the targets since inhibition of a protein that has a maximum flow to resistance genes is more likely to disrupt the communication to these genes. Purposely selected literature review of the top 14 proteins showed that many of them in this list were proposed as drug targets of the pathogen.Electronic supplementary materialThe online version of this article (doi:10.1186/s40169-015-0061-6) contains supplementary material, which is available to authorized users.
Highlights
In spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year
Potential drug targets of Mycobacterium tuberculosis H37Rv were further prioritized based on their maximum flow to the resistance genes to identify those targets in which their inhibition would disrupt communications to these resistance genes in the proteome interaction network
In this study, highly reliable potential drug targets and resistance genes to the existing drugs of Mycobacterium tuberculosis H37Rv were taken as an input and maximum flow approach has been used to prioritize these proteins based on the flow value of each protein to resistance genes
Summary
In spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year. This is mainly due to the emergence of drug-resistance varieties of TB. The current treatment strategies for the drug-resistance TB are of longer duration, more expensive and have side effects. This highlights the importance of identification and prioritization of targets for new drugs. Mycobacterium tuberculosis (Mtb) which is the etiological agent of tuberculosis (TB) remains one of the main health threats of human by being the cause of morbidity and mortality to millions every year [1]. The WHO estimate showed that 3.6 % of the new and 20.2 % of previously
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