Comparative safety and effectiveness of alendronate versus raloxifene in women with osteoporosis
WILEY. 2018: 184
View details for Web of Science ID 000441893801170
- Impact of integrated psycho-socio-economic support on treatment outcome in drug resistant tuberculosis – A retrospective cohort study Indian Journal of Tuberculosis 2018
- Integrated molecular, clinical, and ontological analysis identifies overlooked disease relationships Biorxiv 2017
Learning Effective Treatment Pathways for Type-2 Diabetes from a clinical data warehouse.
AMIA ... Annual Symposium proceedings. AMIA Symposium
2016; 2016: 2036-2042
Treatment guidelines for management of type-2 diabetes mellitus (T2DM) are controversial because existing evidence from randomized clinical trials do not address many important clinical questions. Data from Electronic Medical Records (EMRs) has been used to profile first line therapy choices, but this work did not elucidate the factors underlying deviations from current treatment guidelines and the relative efficacy of different treatment options. We have used data from the Stanford Hospital to attempt to address these issues. Clinical features associated with the initial choice of treatment were effectively re-discovered using a machine learning approach. In addition, the efficacies of first and second line treatments were evaluated using Cox proportional hazard models for control of Hemoglobin A1c. Factors such as acute kidney disorder and liver disorder were predictive of first line therapy choices. Sitagliptin was the most effective second-line therapy, and as effective as metformin as a first line therapy.
View details for PubMedID 28269963
View details for PubMedCentralID PMC5333256
Metformin as a potential combination therapy with existing front-line antibiotics for Tuberculosis
JOURNAL OF TRANSLATIONAL MEDICINE
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) remains a global health concern. The evolution of various multi-drug resistant strains through genetic mutations or drug tolerant strains through bacterial persistence renders existing antibiotics ineffective. Hence there is need for the development of either new antibiotics or rationalizing approved drugs that can be utilized in combination with existing antibiotics as a therapeutic strategy. A comprehensive systems level mapping of metabolic complexity in Mtb revels a putative role of NDH-I in the formation of bacterial persistence under the influence of front-line antibiotics. Possibilities of targeting bacterial NDH-I with existing FDA approved drug for type-II diabetes, Metformin, along with existing front-line antibiotics is discussed and proposed as a potential combination therapy for TB.
View details for DOI 10.1186/s12967-015-0443-y
View details for Web of Science ID 000350869400001
View details for PubMedID 25880846
View details for PubMedCentralID PMC4359515
Systems level mapping of metabolic complexity in Mycobacterium tuberculosis to identify high-value drug targets
JOURNAL OF TRANSLATIONAL MEDICINE
The effectiveness of current therapeutic regimens for Mycobacterium tuberculosis (Mtb) is diminished by the need for prolonged therapy and the rise of drug resistant/tolerant strains. This global health threat, despite decades of basic research and a wealth of legacy knowledge, is due to a lack of systems level understanding that can innovate the process of fast acting and high efficacy drug discovery.The enhanced functional annotations of the Mtb genome, which were previously obtained through a crowd sourcing approach was used to reconstruct the metabolic network of Mtb in a bottom up manner. We represent this information by developing a novel Systems Biology Spindle Map of Metabolism (SBSM) and comprehend its static and dynamic structure using various computational approaches based on simulation and design.The reconstructed metabolism of Mtb encompasses 961 metabolites, involved in 1152 reactions catalyzed by 890 protein coding genes, organized into 50 pathways. By accounting for static and dynamic analysis of SBSM in Mtb we identified various critical proteins required for the growth and survival of bacteria. Further, we assessed the potential of these proteins as putative drug targets that are fast acting and less toxic. Further, we formulate a novel concept of metabolic persister genes (MPGs) and compared our predictions with published in vitro and in vivo experimental evidence. Through such analyses, we report for the first time that de novo biosynthesis of NAD may give rise to bacterial persistence in Mtb under conditions of metabolic stress induced by conventional anti-tuberculosis therapy. We propose such MPG's as potential combination of drug targets for existing antibiotics that can improve their efficacy and efficiency for drug tolerant bacteria.The systems level framework formulated by us to identify potential non-toxic drug targets and strategies to circumvent the issue of bacterial persistence can substantially aid in the process of TB drug discovery and translational research.
View details for DOI 10.1186/s12967-014-0263-5
View details for Web of Science ID 000345167900001
View details for PubMedID 25304862
View details for PubMedCentralID PMC4201925
Social networks to biological networks: systems biology of Mycobacterium tuberculosis
2013; 9 (7): 1584-1593
Contextualizing relevant information to construct a network that represents a given biological process presents a fundamental challenge in the network science of biology. The quality of network for the organism of interest is critically dependent on the extent of functional annotation of its genome. Mostly the automated annotation pipelines do not account for unstructured information present in volumes of literature and hence large fraction of genome remains poorly annotated. However, if used, this information could substantially enhance the functional annotation of a genome, aiding the development of a more comprehensive network. Mining unstructured information buried in volumes of literature often requires manual intervention to a great extent and thus becomes a bottleneck for most of the automated pipelines. In this review, we discuss the potential of scientific social networking as a solution for systematic manual mining of data. Focusing on Mycobacterium tuberculosis, as a case study, we discuss our open innovative approach for the functional annotation of its genome. Furthermore, we highlight the strength of such collated structured data in the context of drug target prediction based on systems level analysis of pathogen.
View details for DOI 10.1039/c3mb25546h
View details for Web of Science ID 000319882200005
View details for PubMedID 23629487
Crowd Sourcing a New Paradigm for Interactome Driven Drug Target Identification in Mycobacterium tuberculosis
2012; 7 (7)
A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D) to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.
View details for DOI 10.1371/journal.pone.0039808
View details for Web of Science ID 000306362400021
View details for PubMedID 22808064
View details for PubMedCentralID PMC3395720
Modeling metabolic adjustment in Mycobacterium tuberculosis upon treatment with isoniazid.
Systems and synthetic biology
2010; 4 (4): 299-309
Complex biological systems exhibit a property of robustness at all levels of organization. Through different mechanisms, the system tries to sustain stress such as due to starvation or drug exposure. To explore whether reconfiguration of the metabolic networks is used as a means to achieve robustness, we have studied possible metabolic adjustments in Mtb upon exposure to isoniazid (INH), a front-line clinical drug. The redundancy in the genome of M. tuberculosis (Mtb) makes it an attractive system to explore if alternate routes of metabolism exist in the bacterium. While the mechanism of action of INH is well studied, its effect on the overall metabolism is not well characterized. Using flux balance analysis, inhibiting the fluxes flowing through the reactions catalyzed by Rv1484, the target of INH, significantly changes the overall flux profiles. At the pathway level, activation or inactivation of certain pathways distant from the target pathway, are seen. Metabolites such as NADPH are shown to reduce drastically, while fatty acids tend to accumulate. The overall biomass also decreases with increasing inhibition levels. Inhibition studies, pathway level clustering and comparison of the flux profiles with the gene expression data indicate the activation of folate metabolism, ubiquinone metabolism, and metabolism of certain amino acids. This analysis provides insights useful for target identification and designing strategies for combination therapy. Insights gained about the role of individual components of a system and their interactions will also provide a basis for reconstruction of whole systems through synthetic biology approaches.The online version of this article (doi:10.1007/s11693-011-9075-6) contains supplementary material, which is available to authorized users.
View details for DOI 10.1007/s11693-011-9075-6
View details for PubMedID 22132057
View details for PubMedCentralID PMC3065594
Protein-protein interaction networks suggest different targets have different propensities for triggering drug resistance.
Systems and synthetic biology
2010; 4 (4): 311-322
Emergence of drug resistance is a major problem in the treatment of many diseases including tuberculosis. To tackle the problem from a wholistic perspective, it is essential to understand the molecular mechanisms by which bacteria acquire drug resistance using a systems approach. Availability of genome-scale data of expression profiles under different drug exposed conditions and protein-protein interactions, makes it feasible to reconstruct and analyze systems-level models. A number of proteins involved in different resistance mechanisms, referred to as the resistome are identified from literature. The interaction of the drug directly with the resistome is unable to explain most resistance processes adequately, including that of increased mutations in the target's binding site. We recently hypothesized that some communication might exist from the drug environment to the resistome to trigger emergence of drug resistance. We report here a network based approach to identify most plausible paths of such communication in Mycobacterium tuberculosis. Networks capturing both structural and functional linkages among various proteins were weighted based on gene expression profiles upon exposure to specific drugs and betweenness centrality of the interactions. Our analysis suggests that different drug targets and hence different drugs could trigger the resistome to different extents and through different routes. The identified paths correlate well with the mechanisms known through experiment. Some examples of the top ranked hubs in multiple drug specific networks are PolA, FadD1, CydA, a monoxygenase and GltS, which could serve as co-targets, that could be inhibited in order to retard resistance related communication in the cell.
View details for DOI 10.1007/s11693-011-9076-5
View details for PubMedID 22132058
View details for PubMedCentralID PMC3065591
Strategies for efficient disruption of metabolism in Mycobacterium tuberculosis from network analysis
2009; 5 (12): 1740-1751
Tuberculosis continues to be a major health challenge, warranting the need for newer strategies for therapeutic intervention and newer approaches to discover them. Here, we report the identification of efficient metabolism disruption strategies by analysis of a reactome network. Protein-protein dependencies at a genome scale are derived from the curated metabolic network, from which insights into the nature and extent of inter-protein and inter-pathway dependencies have been obtained. A functional distance matrix and a subsequent nearness index derived from this information, helps in understanding how the influence of a given protein can pervade to the metabolic network. Thus, the nearness index can be viewed as a metabolic disruptability index, which suggests possible strategies for achieving maximal metabolic disruption by inhibition of the least number of proteins. A greedy approach has been used to identify the most influential singleton, and its combination with the other most pervasive proteins to obtain highly influential pairs, triplets and quadruplets. The effect of deletion of these combinations on cellular metabolism has been studied by flux balance analysis. An obvious outcome of this study is a rational identification of drug targets, to efficiently bring down mycobacterial metabolism.
View details for DOI 10.1039/b905817f
View details for Web of Science ID 000271727600032
View details for PubMedID 19593474