_M. tuberculosis_ interactome analysis unravels potential pathways to drug resistance

Drug resistance is a major problem for combating tuberculosis. Lack of understanding of how resistance emerges in bacteria upon drug treatment limits our ability to counter resistance. By analysis of the _Mycobacterium tuberculosis_ interactome network, along with drug-induced expression data from literature, we show possible pathways for the emergence of drug resistance. To a curated set of resistance related proteins, we have identified sets of high propensity paths from different drug targets. Many top paths were upregulated upon exposure to anti-tubercular drugs. Different targets appear to have different propensities for the four resistance mechanisms. Knowledge of important proteins in such pathways enables identification of appropriate _'co-targets'_, which when simultaneously inhibited with the intended target, is likely to help in combating drug resistance. RecA, Rv0823c, Rv0892 and DnaE1 were the best examples of co-targets for combating tuberculosis. This approach is also inherently generic, likely to significantly impact drug discovery

Collective enhancement and suppression in Bose-Einstein condensates

The coherent and collective nature of Bose-Einstein condensate can enhance or suppress physical processes. Bosonic stimulation enhances scattering in already occupied states which leads to atom amplification, and the suppression of dissipation leads to superfluidity. In this paper, we review several experiments where suppression and enhancement have been observed and discuss the common roots of and differences between these phenomena.Comment: ICAP proceedings; 12 figure

Systems biology

Systems biology seeks to study biological systems as a whole, contrary to the reductionist approach that has dominated biology. Such a view of biological systems emanating from strong foundations of molecular level understanding of the individual components in terms of their form, function and interactions is promising to transform the level at which we understand biology. Systems are defined and abstracted at different levels, which are simulated and analysed using different types of mathematical and computational techniques. Insights obtained from systems level studies readily lend to their use in several applications in biotechnology and drug discovery, making it even more important to study systems as a whol

Mycobacterium tuberculosis interactome analysis unravels potential pathways to drug resistance

<p>Abstract</p> <p>Background</p> <p>Emergence of drug resistant varieties of tuberculosis is posing a major threat to global tuberculosis eradication programmes. Although several approaches have been explored to counter resistance, there has been limited success due to a lack of understanding of how resistance emerges in bacteria upon drug treatment. A systems level analysis of the proteins involved is essential to gain insights into the routes required for emergence of drug resistance.</p> <p>Results</p> <p>We derive a genome-scale protein-protein interaction network for <it>Mycobacterium tuberculosis </it>H37Rv from the STRING database, with proteins as nodes and interactions as edges. A set of proteins involved in both intrinsic and extrinsic drug resistance mechanisms are identified from literature. We then compute shortest paths from different drug targets to the set of resistance proteins in the protein-protein interactome, to derive a sub-network relevant to study emergence of drug resistance. The shortest paths are then scored and ranked based on a new scheme that considers (a) drug-induced gene upregulation data, from microarray experiments reported in literature, for the individual nodes and (b) edge-hubness, a network parameter which signifies centrality of a given edge in the network. High-scoring paths identified from this analysis indicate most plausible pathways for the emergence of drug resistance. Different targets appear to have different propensities for four drug resistance mechanisms. A new concept of 'co-targets' has been proposed to counter drug resistance, co-targets being defined as protein(s) that need to be simultaneously inhibited along with the intended target(s), to check emergence of resistance to a given drug.</p> <p>Conclusion</p> <p>The study leads to the identification of possible pathways for drug resistance, providing novel insights into the problem of resistance. Knowledge of important proteins in such pathways enables identification of appropriate 'co-targets', best examples being RecA, Rv0823c, Rv0892 and DnaE1, for drugs targeting the mycolic acid pathway. Insights obtained about the propensity of a drug to trigger resistance will be useful both for more careful identification of drug targets as well as to identify target-co-target pairs, both implementable in early stages of drug discovery itself. This approach is also inherently generic, likely to significantly impact drug discovery.</p

Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs

Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their growth, survival, and pathogenicity. Mycolic acid biosynthesis has therefore been the focus of a number of biochemical and genetic studies. It also turns out to be the pathway inhibited by front-line anti-tubercular drugs such as isoniazid and ethionamide. Recent years have seen the emergence of systems-based methodologies that can be used to study microbial metabolism. Here, we seek to apply insights from flux balance analyses of the mycolic acid pathway (MAP) for the identification of anti-tubercular drug targets. We present a comprehensive model of mycolic acid synthesis in the pathogen M. tuberculosis involving 197 metabolites participating in 219 reactions catalysed by 28 proteins. Flux balance analysis (FBA) has been performed on the MAP model, which has provided insights into the metabolic capabilities of the pathway. In silico systematic gene deletions and inhibition of InhA by isoniazid, studied here, provide clues about proteins essential for the pathway and hence lead to a rational identification of possible drug targets. Feasibility studies using sequence analysis of the M. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti-tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlate well with those previously identified experimentally through transposon site hybridisation mutagenesis. This study demonstrates the application of FBA for rational identification of potential anti-tubercular drug targets, which can indeed be a general strategy in drug design. The targets, chosen based on the critical points in the pathway, form a ready shortlist for experimental testing

targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis

<p>Abstract</p> <p>Background</p> <p>Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation.</p> <p>Results</p> <p>We report a comprehensive <it>in silico </it>target identification pipeline, targetTB, for <it>Mycobacterium tuberculosis</it>. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of <it>M. tuberculosis </it>are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed.</p> <p>Conclusion</p> <p>The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.</p

Design Fatigue Lives of Polypropylene Fibre Reinforced Polymer Concrete Composites

Flexural fatigue behavior of Poly-propylene fibre reinforced polymer concrete composites (PFRPCC) has been investigated at various stress levels and the statistical analysis of the data thus obtained has been carried out. Polymer Concrete Composite (PCC) samples without addition of any type of fibres were also tested for flexural fatigue.  Forty specimens of PCC and One hundred and Forty One specimens of PFRPCC containing 0.5%, 1.0% and 2.0% polypropylene fibres were tested in fatigue using a MTS servo controlled test system. Fatigue life distributions of PCC as well as PFRPCC are observed to approximately follow a two parameter Weibull distribution with correlation coefficient exceeding 0.9. The parameters of the Weibull distribution have been obtained by various methods. Failure probability, which is an important parameter in the fatigue design of materials, has been used to obtain the design fatigue lives for the material. Comparison of design fatigue life of PCC and PFRPCC has been carried out and it is observed that addition of fibres enhances the design fatigue life of PCC