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Tuberculosis (TB) has become one of the most significant public health problems in recent years. Antibiotic therapy remains the mainstay of TB control strategies, but the increasing resistance of mycobacterial species has heightened alarm, requiring the development of novel drugs in order to improve treatment outcomes. Here, as an effort to identify novel and effective antitubercular agents, we designed and synthesized a series of novel substituted benzimidazolallylidenehydrazinylmethylthiazole derivatives via a multi-component molecular hybridization approach with single molecular architecture. Our design strategy involved assembling the antitubercular pharmacophoric fragments benzimidazole, 2-aminothiazole and substituted α,β-unsaturated ketones via condensation reactions. All the newly synthesized compounds were fully characterized via NMR and mass spectral data and evaluated for in vitro biological activity against the H37Ra strain of Mycobacterium tuberculosis. From the biological evaluation data, we identified some effective compounds, of which 8g and 7e were the most active ones (both having MIC values of 2.5 μg mL(–1)). In addition, compound 8g exhibited a lower cytotoxicity profile. We conceive that compound 8g may serve as a chemical probe of interest for further lead optimization studies with the general aim of developing novel and effective antitubercular agents.

Mycobacterium tuberculosis, a clinically relevant Gram-positive bacterium of great clinical relevance, is a lethal pathogen owing to its complex physiological characteristics and development of drug resistance. Several molecular genetic tools have been developed in the past few decades to study this microorganism. These tools have been instrumental in understanding how M. tuberculosis became a successful pathogen. Advanced molecular genetic tools have played a significant role in exploring the complex pathways involved in M. tuberculosis pathogenesis. Here, we review various molecular genetic tools used in the study of M. tuberculosis. Further, we discuss the applications of clustered regularly interspaced short palindromic repeat interference (CRISPRi), a novel technology recently applied in M. tuberculosis research to study target gene functions. Finally, prospective outcomes of the applications of molecular techniques in the field of M. tuberculosis genetic research are also discussed.

Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a 'difficult to drug' or 'least druggable' target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding. Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2's BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it. Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2's BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers.

Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug into pyrazinoic acid (POA) by Mycobacterium tuberculosis has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report how a new PZA resistance determinant, the Asp67Asn substitution in Rv2783, confers M. tuberculosis resistance to PZA. Expression of the mutant allele but not the wild-type allele in M. tuberculosis recapitulates the PZA resistance observed in clinical isolates. In addition to catalyzing the metabolism of RNA and single-stranded DNA, Rv2783 also metabolized ppGpp, an important signal transducer involved in the stringent response in bacteria. All catalytic activities of the wild-type Rv2783 but not the mutant were significantly inhibited by POA. These results, which indicate that Rv2783 is a target of PZA, provide new insight into the molecular mechanism of the sterilizing activity of this drug and a basis for improving the molecular diagnosis of PZA resistance and developing evolved PZA derivatives to enhance its antituberculosis activity.

This article provides Numerical simulation on forced convective heat transfer performance of Nanofluid flowing through copper helical microtube of inner diameter of 1.5 mm with different pitch using ANSYS-FLUENT 18.0. The simulation was performed for water, CuO/water, Al2O3/water Nanofluid with 1-2% volume concentration and different pitch of microtube (10, 14 and 18 mm) for turbulent flow regime of Reynolds number varied 5000 to 20000 and governing equations of mass, momentum and heat transfer were solved simultaneously, using the k-e two equations turbulence model. Based on the obtained results, regardless of the concentrations used, the nanofluids exhibited a higher transfer rate than water. This is mainly attributed to the nanoparticles that are in the used nanofluids. The friction factor and the heat transfer rate were enhanced considerably due to the shape and size of the tube, which in this case is a helical microtube. Moreover, the maximum heat transfer performance has been conducted by Al2O3/water Nanofluid with 2% volume concentration and microtube pitch of 18 mm.

Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.

IPv4'ten IPv6'ya geçiş beklenen zaman içerisinde gerçekleşmese de, IPv4 adres alanının tükenmesi ve giderek artan internet kullanıcısı sayısı nedeniyle IPv6'ya geçiş kaçınılmazdır. Bu çalışmanın amacı IPv6'ya geçiş için geliştirilen otomatik tünelleme yöntemlerinin, ağ performansını nasıl etkileyeceğidir. Bu tez çalışmasında IPv4, IPv6 ve otomatik tünelleme yöntemlerinden oluşan 6to4 ve ISATAP'ın performans ve kalite açısından karşılaştırılması yapılmıştır. Karşılaştırma benzetim programları kullanılarak sanal ortamda geliştirilmiştir. Ağ verimliliği, jitter ve kayıp paket oranı metrikleri Jperf programı kullanılarak hesaplanmıştır. Transition from IPv4 to IPv6 has not realized as expected, but because of the ever growing demands of internet and depletion of IPv4 address space the transition must be occur. This thesis was aimed at understanding how the transition mechanisms (Automatic Tunneling) will effect to network performance. Tunneling mechanisms will compared in terms of performance with IPv4 and IPv6 in virtual environment by using simulation programs. Parameters such as throughput, jitter and packet loss were evaluated in a lab environment using Jperf 137

This study was carried out to treat the microbial diseases in natural way and reduced the antibiotic resistance pressure. Five species of Lactic acid bacteria namely, L. acidophilus, L. bulgaricus, L. dulbrueckii L. plantarum, and L. fermentum, were isolated from locally produced yogurt. Bacteriocins were isolated from MRS broth culture of theses Lactic acid bacteria through the ammonium sulphate precipitation method. Extracted bacteriocins were tested against test strain i.e E.coli ATCC 25922 to obtain optimum pH, storage temperature and heating temperature for maximum antibacterial activity. For this (2-12) pH range, storage temperatures (-20 °C, 4 °C and 37 °C for 1 month) and heating temperatures (60 °C, 100 °C and 121 °C for 15 minutes) were tested. Later the antibacterial activity of these bacteriocins were tested at concluded optimum conditions against each other as well as against different locally isolated pathogens viz. Methicillin-Resistant-Staphylococcus-aureus, E.coli, Salmonella and Staphylococcus aureus by using well diffusion agar method. It was found that bacteriocins activities were maximum at pH 6 and 4 °C storage temperature. Maximum activity was found after heating bacteriocins at 60 °C as compared to 100 °C and 121 °C. Bacteriocins of lactobacilli were harmless against each other at any pH, heat temperatures and storage temperatures. Antibacterial activity of bacteriocins extracted from L.acidophilus showed maximum activity against pathogenic bacteria as compare to others. The present study has highlighted the antibacterial role of bacteriocins isolated from Lactic acid bacteria by indicating their potential to treat a variety of human and animal diseases.