Artykuły w czasopismach: „Tuberculosis ArgJ”

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Yelamanchi, Soujanya D., Sumaithangi Thattai Arun Kumar, Archita Mishra, Thottethodi Subrahmanya Keshava Prasad i Avadhesha Surolia. "Metabolite Dysregulation by Pranlukast in Mycobacterium tuberculosis". Molecules 27, nr 5 (24.02.2022): 1520. http://dx.doi.org/10.3390/molecules27051520.

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Mycobacterium tuberculosis has been infecting millions of people worldwide over the years, causing tuberculosis. Drugs targeting distinct cellular mechanisms including synthesis of the cell wall, lipids, proteins, and nucleic acids in Mtb are currently being used for the treatment of TB. Although extensive research is being carried out at the molecular level in the infected host and pathogen, the identification of suitable drug targets and drugs remains under explored. Pranlukast, an allosteric inhibitor of MtArgJ (Mtb ornithine acetyltransferase) has previously been shown to inhibit the survival and virulence of Mtb. The main objective of this study was to identify the altered metabolic pathways and biological processes associated with the differentially expressed metabolites by PRK in Mtb. Here in this study, metabolomics was carried out using an LC-MS/MS-based approach. Collectively, 50 metabolites were identified to be differentially expressed with a significant p-value through a global metabolomic approach using a high-resolution mass spectrometer. Metabolites downstream of argJ were downregulated in the arginine biosynthetic pathway following pranlukast treatment. Predicted human protein interactors of pranlukast-treated Mtb metabolome were identified in association with autophagy, inflammation, DNA repair, and other immune-related processes. Further metabolites including N-acetylglutamate, argininosuccinate, L-arginine, succinate, ergothioneine, and L-phenylalanine were validated by multiple reaction monitoring, a targeted mass spectrometry-based metabolomic approach. This study facilitates the understanding of pranlukast-mediated metabolic changes in Mtb and holds the potential to identify novel therapeutic approaches using metabolic pathways in Mtb.

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Gupta, Pooja, Sherine E. Thomas, Shaymaa A. Zaidan, Maria A. Pasillas, James Cory-Wright, Víctor Sebastián-Pérez, Ailidh Burgess i in. "A fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway of Mycobacterium tuberculosis". Computational and Structural Biotechnology Journal 19 (2021): 3491–506. http://dx.doi.org/10.1016/j.csbj.2021.06.006.

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Gordhan, Bhavna G., Debbie A. Smith, Heidi Alderton, Ruth A. McAdam, Gregory J. Bancroft i Valerie Mizrahi. "Construction and Phenotypic Characterization of an Auxotrophic Mutant of Mycobacterium tuberculosis Defective in l-Arginine Biosynthesis". Infection and Immunity 70, nr 6 (czerwiec 2002): 3080–84. http://dx.doi.org/10.1128/iai.70.6.3080-3084.2002.

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ABSTRACT A mutant of Mycobacterium tuberculosis defective in the metabolism of l-arginine was constructed by allelic exchange mutagenesis. The argF mutant strain required exogenous l-arginine for growth in vitro, and in the presence of 0.96 mM l-arginine, it achieved a growth rate and cell density in stationary phase comparable to those of the wild type. The mutant strain was also able to grow in the presence of high concentrations of argininosuccinate, but its auxotrophic phenotype could not be rescued by l-citrulline, suggesting that the ΔargF::hyg mutation exerted a polar effect on the downstream argG gene but not on argH. The mutant strain displayed reduced virulence in immunodeficient SCID mice and was highly attenuated in immunocompetent DBA/2 mice, suggesting that l-arginine availability is restricted in vivo.

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Mattila, Joshua, Olabisi Ojo, Philana Lin i JoAnne Flynn. "Macrophages and neutrophils in necrotic granulomas from cynomolgus macaques and humans localize to distinct microenvironments and express nitric oxide synthase and arginase enzymes. (117.11)". Journal of Immunology 188, nr 1_Supplement (1.05.2012): 117.11. http://dx.doi.org/10.4049/jimmunol.188.supp.117.11.

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Abstract Macrophages are abundant in granulomas, the hallmark lesion of tuberculosis (TB), where they engage in activities critical for mycobacterial control. The assortment of macrophage functions, ranging from being the primary anti-mycobacterial effector cell to the primary mycobacterial host cell, underscores the complexity of macrophages in this system. Despite their importance, the molecular phenotypes and functions of granuloma macrophages in human TB are not well understood. In this study, we examined a variety of macrophage markers in non-human primate and human granulomas to better describe macrophage diversity and spatial organization. We identified three myeloid cell markers, including CD68, CD163, and HAM56, that stained populations of macrophages occupying discrete positions in necrotic granulomas that may be relevant to granuloma function. Neutrophils expressed high levels of calprotectin, a small bacteriostatic protein sometimes associated with macrophages, and also localized to specific positions in necrotic granulomas. In addition to phenotypic markers, we identified cell-specific expression of nitric oxide synthase isoforms (iNOS and eNOS) and arginase isoforms (arg1 and arg2) expression in granulomas by biochemical, molecular and immunohistochemical techniques. Both macrophages and neutrophils were determined to express NOS and arg enzymes, including co-expression, suggesting these enzymes with opposing effects act in concert to maintain mycobacterial control.

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Mtetwa, Hlengiwe N., Isaac D. Amoah, Sheena Kumari, Faizal Bux i Poovendhree Reddy. "Wastewater-Based Surveillance of Antibiotic Resistance Genes Associated with Tuberculosis Treatment Regimen in KwaZulu Natal, South Africa". Antibiotics 10, nr 11 (8.11.2021): 1362. http://dx.doi.org/10.3390/antibiotics10111362.

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Essential components of public health include strengthening the surveillance of infectious diseases and developing early detection and prevention policies. This is particularly important for drug-resistant tuberculosis (DR-TB), which can be explored by using wastewater-based surveillance. This study aimed to use molecular techniques to determine the occurrence and concentration of antibiotic-resistance genes (ARGs) associated with tuberculosis (TB) resistance in untreated and treated wastewater. Raw/untreated and treated (post-chlorination) wastewater samples were taken from three wastewater treatment plants (WWTPs) in South Africa. The ARGs were selected to target drugs used for first- and second-line TB treatment. Both conventional polymerase chain reaction (PCR) and the more advanced droplet digital PCR (ddPCR) were evaluated as surveillance strategies to determine the distribution and concentration of the selected ARGs. The most abundant ARG in the untreated wastewater was the rrs gene, associated with resistance to the aminoglycosides, specifically streptomycin, with median concentration ranges of 4.69–5.19 log copies/mL. In contrast, pncA gene, associated with resistance to the TB drug pyrazinamide, was the least detected (1.59 to 2.27 log copies/mL). Resistance genes associated with bedaquiline was detected, which is a significant finding because this is a new drug introduced in South Africa for the treatment of multi-drug resistant TB. This study, therefore, establishes the potential of molecular surveillance of wastewater for monitoring antibiotic resistance to TB treatment in communities.

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Su, Sicong, Chenyu Li, Jiping Yang, Qunying Xu, Zhigang Qiu, Bin Xue, Shang Wang i in. "Distribution of Antibiotic Resistance Genes in Three Different Natural Water Bodies-A Lake, River and Sea". International Journal of Environmental Research and Public Health 17, nr 2 (15.01.2020): 552. http://dx.doi.org/10.3390/ijerph17020552.

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Currently, due to abuse in the use of human antibiotics and the weak regulatory control that the authorities have over sewage discharge and manure management, antibiotic resistance genes (ARGs) have become a new type of environmental pollutant. Three different natural water bodies (Poyang Lake, Haihe River and Qingdao No.1 Bathing Beach seawater) were sampled during the same periods to conduct a longitudinal comparison of distribution. The distribution and expression of 11 ARGs in 20 species were studied, and the correlations between the expression and the distribution of time and space of the ARGs in different water bodies were also analyzed. With the exception of ermA, blaNDM-1 and vanA, which were not detected in seawater, the other ARGs could be detected in all three water bodies. Tetracycline resistance genes (tetC, tetM and tetQ) in the seawater and Haihe River had even reached 100%, and sulfa ARGs (sul1 and sul2) in the seawater and Poyang Lake, as well as sul2 and sul3 in the Haihe River, had also reached 100%. The ARG pollution in Haihe River was much more serious, since 14 and 17 of 20 ARG species were significantly higher compared with seawater and Poyang Lake, respectively. Some ARGs also had a high absolute abundance. The absolute abundance of macrolide resistance genes (ermB) in seawater was as high as 8.61 × 107 copies/L, and the anti-tuberculosis resistant genes (rpoB and katG) in the Haihe River Basin were highly abundant at 1.32 × 106 copies/L and 1.06 × 107 copies/L, respectively. This indicates that ARGs have gradually become more diverse and extensive in natural water bodies. The results of a redundancy analysis (RDA) of the three water bodies showed that although each water body is affected by different factors in space and time, overall, the presence of AGRs is closely related to the production and life of human beings and the migration of animals.

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Tiwari, Sangeeta, Andries J. van Tonder, Catherine Vilchèze, Vitor Mendes, Sherine E. Thomas, Adel Malek, Bing Chen i in. "Arginine-deprivation–induced oxidative damage sterilizes Mycobacterium tuberculosis". Proceedings of the National Academy of Sciences 115, nr 39 (24.08.2018): 9779–84. http://dx.doi.org/10.1073/pnas.1808874115.

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Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants ΔargB and ΔargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. ΔargB and ΔargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, our investigation revealed in vivo essentiality of the de novo arginine biosynthesis pathway for Mtb and a promising drug target space for combating tuberculosis.

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Qualls, Joseph E., Ashley DeFreitas, Amber M. Smith, Stephanie S. Watowich i Peter J. Murray. "Direct and indirect type-1 arginase (Arg1) induction following Mycobacterium bovis (BCG) infection (43.1)". Journal of Immunology 182, nr 1_Supplement (1.04.2009): 43.1. http://dx.doi.org/10.4049/jimmunol.182.supp.43.1.

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Abstract M. tuberculosis infects lung macrophages (MØs) and evades immune responses by a diverse array of mechanisms. We have recently published that BCG infection triggers a MyD88-dependent Arg1 induction that suppresses NO production from infected MØs. In addition, MØ-specific Arg1 conditional knockout mice were more efficient at clearing M. tuberculosis and BCG. In the present study, we have found that while MyD88 is essential for Arg1 induction following infection, MyD88-/- MØs express robust Arg1 mRNA and protein when stimulated with supernatant from BCG-infected WT MØs. Arg1 induction stimulated with BCG supernatant correlated with enhanced activation of Stat3, but not Stat1, 4, 5, or 6. Two Stat3 activators, IL-6 and IL-10, were present in the supernatants of BCG infected WT MØs. We found the combined treatment of MØs with IL-6 and IL-10 synergistically induces Arg1 in the presence or absence of BCG infection. Consequently, we propose a model by which Arg1 is induced directly by BCG infection via MyD88 signaling, and indirectly through the autocrine/paracrine IL-6/IL-10 activation of Stat3. These data suggest that mycobacteria can condition uninfected neighboring cells to suppress NO production.

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Pasula, Rajamouli, Paul Wisniowski i William J. Martin. "Fibronectin Facilitates Mycobacterium tuberculosis Attachment to Murine Alveolar Macrophages". Infection and Immunity 70, nr 3 (marzec 2002): 1287–92. http://dx.doi.org/10.1128/iai.70.3.1287-1292.2002.

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ABSTRACT Mycobacterium tuberculosis remains a major cause of pulmonary infection worldwide. Attachment of M. tuberculosis organisms to alveolar macrophages (AMs) represents the earliest phase of primary infection in pulmonary tuberculosis. In this study fibronectin (Fn), an adhesive protein, is shown to bind M. tuberculosis organisms and facilitates attachment of M. tuberculosis to murine AMs. A monoclonal antibody (MAb) specific to the heparin binding domain (HBD) of Fn decreases 125I-Fn binding to M. tuberculosis; whereas MAbs specific to either the cell binding domain (CBD) or the gelatin binding domain (GBD) have no effect on Fn binding to M. tuberculosis. In the presence of exogenous Fn (10 μg/ml) M. tuberculosis attachment to AMs increased significantly from control levels (means ± standard errors of the means) of 11.5% ± 1.1% to 44.2% ± 4.2% (P < 0.05). Fn-enhanced attachment was significantly decreased from 44.2% ± 4.2% to 10.8% ± 1.2% (P < 0.05) in the presence of anti-Fn polyclonal antibodies. The attachment is also inhibited in the presence of MAbs specific for the HBD and CBD, whereas MAbs specific to GBD did not affect the attachment. Further, an Fn cell binding peptide, Arg-Gly-Asp-Ser (RGDS), decreased the attachment from 44.2% ± 4.2% to 15.3% ± 1.2% (P < 0.05), whereas addition of a control peptide, Arg-Gly-Glu-Ser (RGES) did not affect the attachment (40.5% ± 1.8%). These results suggest that Fn-mediated attachment of M. tuberculosis can occur through the binding of Fn to the AM via the CBD and to M. tuberculosis organisms via the HBD.

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Crowther, Rebecca R., Stephanie M. Schmidt, Junfang Zhao, Melanie C. McKell, Kenneth D. Setchell i Joseph E. Qualls. "Dendritic Cells Supply CD4+ T Cells With L-arginine". Journal of Immunology 206, nr 1_Supplement (1.05.2021): 53.03. http://dx.doi.org/10.4049/jimmunol.206.supp.53.03.

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Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, is responsible for over 1 million deaths each year. Mycobacteria-infected dendritic cells (DCs) migrate to the lymph node to initiate adaptive immune priming, which is vital to antimycobacterial immunity. This response is intimately tied to nutrient availability – especially the amino acid L-arginine (L-ARG), metabolism of which is altered in TB patients. We have characterized a pathway utilized by immune cells to synthesize L-ARG. Loss of L-ARG synthesis in CD11c+ cells, which includes DCs, results in increased mycobacterial burden following infection in mice. To characterize the role of this pathway in DCs, we developed a co-culture system with mycobacterial-specific CD4+ T cells and bone marrow derived DCs. Using CD4+ T cells and DCs with differing capabilities of L-ARG synthesis, we found 1) DC L-ARG synthesis supports CD4+ T cell proliferation and 2) activated T cells contain DC-derived L-ARG. We hypothesize DCs “share” synthesized L-ARG to support CD4+ T cell activation when L-ARG is limiting. Our data suggest nutrient availability as a 4th signal – following antigen presentation, co-stimulation, and cytokine receptor ligation – required for T cell activation. This work expands the current model of DC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.

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Errey, James C., i John S. Blanchard. "Functional Characterization of a Novel ArgA from Mycobacterium tuberculosis". Journal of Bacteriology 187, nr 9 (1.05.2005): 3039–44. http://dx.doi.org/10.1128/jb.187.9.3039-3044.2005.

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ABSTRACT The Mycobacterium tuberculosis gene Rv2747 encodes a novel 19-kDa ArgA that catalyzes the initial step in l-arginine biosynthesis, namely the conversion of l-glutamate to α-N-acetyl-l-glutamate. Initial velocity studies reveal that Rv2747 proceeds through a sequential kinetic mechanism, with Km values of 280 mM for l-glutamine and 150 μM for acetyl-coenzyme A and with a k cat value of 200 min−1. Initial velocity studies with l-glutamate showed that even at concentrations of 600 mM, saturation was not observed. Therefore, only a k cat/Km value of 125 M−1 min−1 can be calculated. Inhibition studies reveal that the enzyme is strongly regulated by l-arginine, the end product of the pathway (50% inhibitory concentration, 26 μM). The enzyme was completely inhibited by 500 μM arginine, with a Hill coefficient of 0.60, indicating negatively cooperative binding of l-arginine.

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Napolitano, Danielle R., Nira Pollock, Suely S. Kashino, Virmondes Rodrigues i Antonio Campos-Neto. "Identification of Mycobacterium tuberculosis Ornithine Carboamyltransferase in Urine as a Possible Molecular Marker of Active Pulmonary Tuberculosis". Clinical and Vaccine Immunology 15, nr 4 (27.02.2008): 638–43. http://dx.doi.org/10.1128/cvi.00010-08.

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ABSTRACT Although the antigen detection assay has the potential to discriminate active tuberculosis from latent infection, development of such a test for the accurate diagnosis of this serious disease has only recently become a matter of interest. Here we present evidence that a Mycobacterium tuberculosis protein (ornithine carboamyltransferase, coded for by MT_1694; Rv1656 [argF]) is an interesting candidate molecule for this test development. The protein was initially discovered by mass spectroscopy in urine of patients with pulmonary tuberculosis and shown by Western blot analysis to be present in M. tuberculosis crude cell extract as well as in the culture supernatant (“secreted” protein). In addition, a recombinant ornithine carboamyltransferase (rMT1694) produced in Escherichia coli was recognized by immunoglobulin G (IgG) antibodies from patients with active tuberculosis but not by IgG from uninfected healthy subjects. Moreover, rMT1694 was strongly recognized by peripheral blood mononuclear cells from both healthy tuberculin purified protein derivative (PPD)-positive individuals and patients with pulmonary tuberculosis. More importantly, a capture enzyme-linked immunosorbent assay formatted with rabbit IgG antibodies specific to rMT1694 was able to identify the presence of this antigen in urine samples from 6 of 16 patients with pulmonary tuberculosis and in none of 16 urine samples collected from healthy PPD+ controls. These results indicate that an improved antigen detection assay based on M. tuberculosis ornithine carboamyltransferase may represent an important new strategy for the development of a specific and accurate diagnostic test for tuberculosis.

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Walter, Nicholas D., Bouke C. de Jong, Benjamin J. Garcia, Gregory M. Dolganov, William Worodria, Patrick Byanyima, Emmanuel Musisi i in. "Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients". Journal of Infectious Diseases 214, nr 8 (17.08.2016): 1205–11. http://dx.doi.org/10.1093/infdis/jiw364.

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AbstractBackground. It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis in vivo. We evaluated the impact of host immunity by comparing M. tuberculosis and human gene transcription in sputum between human immunodeficiency virus (HIV)–infected and uninfected patients with tuberculosis.Methods. We collected sputum specimens before treatment from Gambians and Ugandans with pulmonary tuberculosis, revealed by positive results of acid-fast bacillus smears. We quantified expression of 2179 M. tuberculosis genes and 234 human immune genes via quantitative reverse transcription–polymerase chain reaction. We summarized genes from key functional categories with significantly increased or decreased expression.Results. A total of 24 of 65 patients with tuberculosis were HIV infected. M. tuberculosis DosR regulon genes were less highly expressed among HIV-infected patients with tuberculosis than among HIV-uninfected patients with tuberculosis (Gambia, P < .0001; Uganda, P = .037). In profiling of human genes from the same sputa, HIV-infected patients had 3.4-fold lower expression of IFNG (P = .005), 4.9-fold higher expression of ARG1 (P = .0006), and 3.4-fold higher expression of IL10 (P = .0002) than in HIV-uninfected patients with tuberculosis.Conclusions. M. tuberculosis in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by NO, carbon monoxide, and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages, with consequent decreased NO expression and/or by poor granuloma formation with consequent decreased hypoxic stress.

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Bashiri, Ghader, Laura V. Nigon, Ehab N. M. Jirgis, Ngoc Anh Thu Ho, Tamsyn Stanborough, Stephanie S. Dawes, Edward N. Baker, Esther M. M. Bulloch i Jodie M. Johnston. "Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis". Journal of Biological Chemistry 295, nr 12 (6.02.2020): 3759–70. http://dx.doi.org/10.1074/jbc.ra119.012158.

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Menaquinone (vitamin K2) plays a vital role in energy generation and environmental adaptation in many bacteria, including the human pathogen Mycobacterium tuberculosis (Mtb). Although menaquinone levels are known to be tightly linked to the cellular redox/energy status of the cell, the regulatory mechanisms underpinning this phenomenon are unclear. The first committed step in menaquinone biosynthesis is catalyzed by MenD, a thiamine diphosphate–dependent enzyme comprising three domains. Domains I and III form the MenD active site, but no function has yet been ascribed to domain II. Here, we show that the last cytosolic metabolite in the menaquinone biosynthesis pathway, 1,4-dihydroxy-2-naphthoic acid (DHNA), binds to domain II of Mtb-MenD and inhibits its activity. Using X-ray crystallography of four apo- and cofactor-bound Mtb-MenD structures, along with several spectroscopy assays, we identified three arginine residues (Arg-97, Arg-277, and Arg-303) that are important for both enzyme activity and the feedback inhibition by DHNA. Among these residues, Arg-277 appeared to be particularly important for signal propagation from the allosteric site to the active site. This is the first evidence of feedback regulation of the menaquinone biosynthesis pathway in bacteria, identifying a protein-level regulatory mechanism that controls menaquinone levels within the cell and may therefore represent a good target for disrupting menaquinone biosynthesis in M. tuberculosis.

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Yang, Xiuna, Lijie Wu, Yajun Ran, Ao Xu, Bing Zhang, Xiaolin Yang, Rongguang Zhang, Zihe Rao i Jun Li. "Crystal structure of l -glutamate N -acetyltransferase ArgA from Mycobacterium tuberculosis". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1865, nr 12 (grudzień 2017): 1800–1807. http://dx.doi.org/10.1016/j.bbapap.2017.09.009.

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El-Masry, Eman A., Ibrahim Taher, Helal F. Hetta i Samy S. Eldahdouh. "Pulmonary tuberculosis susceptibility and association with Toll-Like receptor 2 Arg753Gln polymorphism". Journal of Infection in Developing Countries 16, nr 01 (31.01.2022): 125–33. http://dx.doi.org/10.3855/jidc.14885.

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Introduction: Tuberculosis has been a concern of healthcare professionals due to the serious threats it poses on public health safety. However, regardless all the efforts, no appropriate goals for immunological diagnosis or tuberculosis treatment were established. Toll-like receptor 2 is one of the toll-like receptors, which plays a fundamental role in recognizing and hosting defense against Mycobacterium tuberculosis infection. Toll-like receptor 2’s genetic polymorphism (arginine-to-glutamine substitution at residue 753 (Arg753Gln)) was linked to negative effects on the function of Toll-like receptor 2 which, in turn, impacts the body’s resistance or susceptibility to tuberculosis. The current study aimed at investigating the single Arg753Gln nucleotide polymorphism of the Toll-like receptor 2 gene in patients with tuberculosis infection versus a sample of healthy subjects as controls. Methodology: A comparative study was conducted to investigate Toll-like receptor 2 polymorphism of the single nucleotide gene Arg753Gln in 30 patients with pulmonary tuberculosis and compare their results with other 20 healthy controls matched by age and sex. Results: TLR-2-Arg polymorphism allele A occurred in 36.7% of the patient group. Homozygous carriers of allele A/A polymorphism occurred in 13.4% compared to 5% among controls, while GA genotype was found in 23.3% among the study group and 10% among controls. The association between GA genotype and pulmonary tuberculosis was found statistically significant (p = 0.002) than other genotypes. Allele frequency for both G and A were (p =0.002) in patient groups and (p =0.000) among the control group. Conclusions: TLR-2 Arg753Gln polymorphisms may have a crucial role in pulmonary tuberculosis susceptibility among Egyptian patients.

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Nagel, Raimund, Jill Thomas, Faith Adekunle, Francis Mann i Reuben Peters. "Arginine in the FARM and SARM: A Role in Chain-Length Determination for Arginine in the Aspartate-Rich Motifs of Isoprenyl Diphosphate Synthases from Mycobacterium tuberculosis". Molecules 23, nr 10 (6.10.2018): 2546. http://dx.doi.org/10.3390/molecules23102546.

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Isoprenyl chains are found in many important metabolites. These are derived from precursors of the appropriate length produced by isoprenyl diphosphate synthases (IDSs). The human pathogen Mycobacterium tuberculosis makes various isoprenoids/terpenoids, with important roles in their biosynthesis played by two closely related IDSs, encoded by grcC1 (Rv0562) and grcC2 (Rv0989c), with Rv0989c generating the 10-carbon precursor (E)-geranyl diphosphate (GPP), and Rv0562 the 20-carbon precursor (E,E,E)-geranylgeranyl diphosphate (GGPP). Intriguingly, while Rv0562 contains the prototypical trans-IDS first and second aspartate-rich (DDxxD) motifs (FARM and SARM, respectively), Rv0989c uniquely contains arginine in place of the second Asp in the FARM and first Asp in the SARM. Here site-directed mutagenesis of the corresponding residues in both Rv0562 and Rv0989c reveals that these play a role in determination of product chain length. Specifically, substitution of Asp for the Arg in the FARM and SARM of Rv0989c leads to increased production of the longer 15-carbon farnesyl diphosphate (FPP), while substitution of Arg for the corresponding Asp in Rv0562 leads to increased release of shorter products, both FPP and GPP. Accordingly, while the primary role of the FARM and SARM is known to be chelation of the divalent magnesium ion co-factors that assist substrate binding and catalysis, the Arg substitutions found in Rv0989c seem to provide a novel means by which product chain length is moderated, at least in these M. tuberculosis IDSs.

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Hou, Meijing, Jie Zhuang, Shihui Fan, Huilin Wang, Chenyun Guo, Hongwei Yao, Donghai Lin i Xinli Liao. "Biophysical and functional characterizations of recombinant RimI acetyltransferase from Mycobacterium tuberculosis". Acta Biochimica et Biophysica Sinica 51, nr 9 (7.08.2019): 960–68. http://dx.doi.org/10.1093/abbs/gmz075.

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Abstract Nα-acetylation is a universal protein modification related to a wide range of physiological processes in eukaryotes and prokaryotes. RimI, an Nα-acetyltransferase in Mycobacterium tuberculosis, is responsible for the acetylation of the α-amino group of the N-terminal residue in the ribosomal protein S18. Despite growing evidence that protein acetylation may be correlated with the pathogenesis of tuberculosis, no structural information is yet available for mechanistically understanding the MtRimI acetylation. To enable structural studies for MtRimI, we constructed a serial of recombinant MtRimI proteins and assessed their biochemical properties. We then chose an optimal construct MtRimIC21A4-153 and expressed and purified the truncated high-quality protein for further biophysical and functional characterizations. The 2D 1H-15N heteronuclear single quantum coherence spectrum of MtRimIC21A4-153 exhibits wider chemical shift dispersion and favorable peak isolation, indicating that MtRimIC21A4-153 is amendable for further structural determination. Moreover, bio-layer interferometry experiments showed that MtRimIC21A4-153 possessed similar micromolar affinity to full-length MtRimI for binding the hexapeptide substrate Ala-Arg-Tyr-Phe-Arg-Arg. Enzyme kinetic assays also exhibited that MtRimIC21A4-153 had almost identical enzymatic activity to MtRimI, indicating insignificant influence of the recombinant variations on enzymatic functions. Furthermore, binding sites of the peptide were predicted by molecular docking approach, suggesting that this substrate binds to MtRimI primarily through electrostatic and hydrogen bonding interactions. Our results lay a foundation for the further structural determination and dynamics detection of MtRimI.

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Das, Uddipan, Ekta Singh, Sudhaker Dharavath, Udaya Kumar Tiruttani Subhramanyam, Ravi Kant Pal, Ramachandran Vijayan, Saji Menon, Saroj Kumar, Samudrala Gourinath i Alagiri Srinivasan. "Structural insights into the substrate binding mechanism of novel ArgA from Mycobacterium tuberculosis". International Journal of Biological Macromolecules 125 (marzec 2019): 970–78. http://dx.doi.org/10.1016/j.ijbiomac.2018.12.163.

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Billington, O. J., T. D. McHugh i S. H. Gillespie. "Physiological Cost of Rifampin Resistance Induced In Vitro in Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy 43, nr 8 (1.08.1999): 1866–69. http://dx.doi.org/10.1128/aac.43.8.1866.

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ABSTRACT Drug-resistant Mycobacterium tuberculosis is a major threat to public health. In clinical practice, a limited number of resistance mutations in a short sequence of the beta subunit of RNA polymerase (encoded by rpoB) have been described. Spontaneous resistance to rifampin was induced in vitro in M. tuberculosis H37Rv (ATCC 9360). Only three resistance patterns could be detected by PCR–single-strand conformation polymorphism analysis. Sequence analysis revealed that Ser531→Leu arose most frequently, followed by His526→Arg and then either His526→Tyr or His526→Asp. The relative Darwinian fitness of all but one of the mutant genotypes was less than that of the susceptible parent and, for these mutations, there was a significant correlation between fitness and clinical isolation rate (regression analysis P = 0.026). The fitness deficit in some mutants was small, suggesting that there is little likelihood of a spontaneous reversion to susceptibility.

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Marquis, Jean-François, André Nantel, Ronald LaCourse, Lynn Ryan, Robert J. North i Philippe Gros. "Fibrotic Response as a Distinguishing Feature of Resistance and Susceptibility to Pulmonary Infection with Mycobacterium tuberculosis in Mice". Infection and Immunity 76, nr 1 (15.10.2007): 78–88. http://dx.doi.org/10.1128/iai.00369-07.

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ABSTRACT The differential susceptibility of inbred mouse strains DBA/2J (susceptible) and C57BL/6J (resistant) to pulmonary tuberculosis following aerosol infection is under complex genetic control. In this report, transcriptional profiling with RNAs from Mycobacterium tuberculosis-infected lungs was used to investigate the physiological response, cell type, and biochemical pathways underlying differential susceptibility to infection. Statistical analysis of cDNA-based microarrays revealed that 1,097 transcripts showed statistically significant changes in abundance (changes of ≥1.5-fold) in at least one of four experimental group comparisons (C57BL/6J [day 0] versus DBA/2J [day 0] mice, C57BL/6J [day 90] versus DBA/2J [day 90] mice, C57BL/6J [day 90] versus C57BL/6J [day 0] mice, or DBA/2J [day 90] versus DBA/2J [day 0] mice). A group of genes showing very high degrees of significance (changes of ≥2.0-fold) displayed enrichment for transcripts associated with tissue remodeling and the fibrotic response. The differential expression of fibrotic response genes (Sparc, Col1a1, Col1a2, Col4a1, and Col4a2) in the infected lungs of the two mouse strains was validated by another microarray platform (Affymetrix oligonucleotide chips) and by reverse transcription-PCR. Furthermore, the differential expression of additional genes known to be associated with fibrosis (Mmp2, Timp1, and Arg1) was also validated by these approaches. Overall, these results identify the differential fibrotic response as a pathological basis for the high susceptibility of DBA/2J mice to pulmonary tuberculosis.

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Vecchione, James J., Blair Alexander i Jason K. Sello. "Two Distinct Major Facilitator Superfamily Drug Efflux Pumps Mediate Chloramphenicol Resistance in Streptomyces coelicolor". Antimicrobial Agents and Chemotherapy 53, nr 11 (17.08.2009): 4673–77. http://dx.doi.org/10.1128/aac.00853-09.

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ABSTRACT Chloramphenicol, florfenicol, and thiamphenicol are used as antibacterial drugs in clinical and veterinary medicine. Two efflux pumps of the major facilitator superfamily encoded by the cmlR1 and cmlR2 genes mediate resistance to these antibiotics in Streptomyces coelicolor, a close relative of Mycobacterium tuberculosis. The transcription of both genes was observed by reverse transcription-PCR. Disruption of cmlR1 decreased the chloramphenicol MIC 1.6-fold, while disruption of cmlR2 lowered the MIC 16-fold. The chloramphenicol MIC of wild-type S. coelicolor decreased fourfold and eightfold in the presence of reserpine and Phe-Arg-β-naphthylamide, respectively. These compounds are known to potentiate the activity of some antibacterial drugs via efflux pump inhibition. While reserpine is known to potentiate drug activity against gram-positive bacteria, this is the first time that Phe-Arg-β-naphthylamide has been shown to potentiate drug activity against a gram-positive bacterium.

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Zhang, Yanhao, Shanshan Li, Qianyi Liu, Ruiying Long, Jihong Feng, Huan Qin, Mao Li, Liping Liu i Junmin Luo. "Mycobacterium tuberculosis Heat-Shock Protein 16.3 Induces Macrophage M2 Polarization Through CCRL2/CX3CR1". Inflammation 43, nr 2 (20.11.2019): 487–506. http://dx.doi.org/10.1007/s10753-019-01132-9.

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Abstract Mycobacterium tuberculosis, the pathogen of tuberculosis (TB), can survive in host macrophages and induce macrophages to M2 phenotype might result in latent MTB infection. During the latent phase, the expression of MTB heat-shock protein 16.3 (Hsp16.3) is markedly increased among most of bacterial proteins, but the role of Hsp16.3 in macrophage M2 polarization is not clear. In this work, we found that macrophages incubated with 100 ng/ml MTB Hsp16.3 increased the production of Arg-1, IL-10, TGF-beta, and CD206. These results showed that MTB Hsp16.3 may induce macrophage M2 phenotype. And the interaction of Hsp16.3 with macrophages was found to depend on chemokine receptors CCRL2 and CX3CR1. Additionally, we used overexpression and silencing techniques to further verify the effect of CCRL2 and CX3CR1 on MTB Hsp16.3-induced M2 polarization macrophages. Furthermore, we explored the downstream signaling molecules of CCRL2 and CX3CR1 and we found MTB Hsp16.3 altered the signal transduction of the AKT/ERK/p38-MAPK. Taken together, this study provides evidence that MTB Hsp16.3 promotes macrophages to M2 phenotype and explores its underlying mechanism.

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Alfred Maroyi. "Croton mubango Müll. Arg.: Its Botany, Ethnomedicinal Uses and Pharmacological Properties". Journal of Pharmacy and Nutrition Sciences 8, nr 4 (5.09.2018): 178–84. http://dx.doi.org/10.29169/1927-5951.2018.08.04.4.

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Croton mubango is widely used as traditional medicine in tropical Africa. The potential of C. mubango as traditional medicine, its botany, chemical and pharmacological activities are reviewed. The literature relevant to the study was obtained from scientific databases such as BioMed Central (BMC), Web of Science, Google Scholar, Scopus, Science Direct, PubMed, Springerlink and Scielo. Other supplementary literature such as books, book chapters, theses, conference papers and other scientific publications were obtained from the University of Fort Hare Library and dissertation search engines such as EThOS, OATD, ProQuest and Open-thesis. Literature search revealed that the bark, fruits, leaves and roots of C. mubango are commonly used as traditional medicines for abdominal pain, diarrhoea, dysentery, fever, hernia, intestinal worms, malaria, rheumatism, toothache, tuberculosis and as purgative. Phytochemical compounds isolated from C. mubango include alkaloids, flavonoids, reducing sugars, saponins, steroids, tannins, terpenes and triterpenes. Pharmacological studies on C. mubango indicate that the species has in vitro and in vivo antiplasmodial activities. Several medicinal applications and therapeutic potentials of C. mubango have been demonstrated in this study although the majority of them still need pharmacological validation.

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Khurana, Harleen, Mitul Srivastava, Deepika Chaudhary, Tannu Priya Gosain, Raniki Kumari, Andrew C. Bean, Saurabh Chugh i in. "Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis". International Journal of Biological Macromolecules 193 (grudzień 2021): 1845–58. http://dx.doi.org/10.1016/j.ijbiomac.2021.11.017.

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Kumar, Abhishek, Meenu Patil, Pardeep Kumar, Ram Chand Bhatti, Rupinder Kaur, Nitin Kumar Sharma i Anand Narain Singh. "Mallotus philippensis (Lam.) Müll. Arg.: A review on its pharmacology and phytochemistry". Journal of Herbmed Pharmacology 10, nr 1 (20.10.2020): 31–50. http://dx.doi.org/10.34172/jhp.2021.03.

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Kamala tree (Mallotus philippensis) is traditionally used by different ethnic groups to treat a variety of diseases and health ailments. However, these traditional uses need to be scientifically investigated and validated in order to develop drugs from this tree. Therefore, the present article is aimed to review the scientifically validated knowledge on the pharmacology and phytochemistry of the tree. To accomplish this, we extensively surveyed the available databases like Scopus, Web of Science, Google Scholar, ScienceDirect, NCBI including PubMed and PubChem, etc. by using keywords ‘Mallotus philippensis’, ‘Mallotus phillippinensis’ and ‘Mallotus philippinensis’. Our results indicated that the tree possesses more than 50 different types of important phytochemicals of natural origin. The wide array of phytochemicals possesses fascinating biological activities like anthelmintic, antibacterial, anti-inflammatory, anti-oxidant, anti-cancerous, anti-tuberculosis, anti-parasitic, analgesic, anti-urolithiatic and anti-viral activities. Thus, pharmacological activities and isolation of active phytochemicals make the tree a promising candidate for drug discovery. However, pharmacological activities such as antibacterial and anti-oxidant activities are often tested with crude extracts and in vitro rudimentary methods that can be sometimes misleading and non-specific. Thus, more sophisticated techniques may be applied for the isolation of active chemicals and elucidating their mechanism of actions.

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Nehvi, Iqra Bashir, Neha Quadir, Mohd Khubaib, Javaid Ahmad Sheikh, Mohd Shariq, Krishnaveni Mohareer, Sharmistha Banerjee, Syed Asad Rahman, Nasreen Z. Ehtesham i Seyed E. Hasnain. "ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator". International Journal of Medical Microbiology 312, nr 1 (styczeń 2022): 151544. http://dx.doi.org/10.1016/j.ijmm.2021.151544.

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Radhakrishnan, Rajesh Kumar, Ramya Sivangala Thandi, Deepak Tripathi, Padmaja Paidipally, Madeline McAllister, Sachin Mulik, Buka Samten i Ramakrishna Vankayalapati. "BCG vaccination reduces the mortality of Mycobacterium tuberculosis-infected type 2 diabetes mellitus (T2DM) mice through the induction of CXCR3+ T-regulatory cells". Journal of Immunology 204, nr 1_Supplement (1.05.2020): 85.11. http://dx.doi.org/10.4049/jimmunol.204.supp.85.11.

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Abstract Diabetes is a significant risk factor for the development of active tuberculosis. In this study, we used mouse model of Streptozotocin/Nicotinamide (STZ/NA) induced non-obese type 2 diabetes mellitus (T2DM) to determine the effect of prior BCG vaccination on survival and immune responses to Mycobacterium tuberculosis (Mtb) infection. We found that at 6–7 months post-Mtb infection, 90% of the Mtb-infected T2DM mice died, whereas only 50% of BCG-vaccinated T2DM-Mtb-infected mice died. Moreover, 40% of the PBS-treated uninfected T2DM mice and 30% of the uninfected BCG-vaccinated T2DM mice died, whereas all uninfected and infected nondiabetic mice survived. BCG vaccination was less effective in reducing the lung bacterial burden of Mtb infected T2DM mice compared to Mtb-infected non-diabetic mice, however it reduced immunopathology of lung tissues. Further, we found increased survival of BCG vaccinated Mtb infected T2DM mice is associated with 2-fold expansion of IL-13 producing CXCR3+ T-regulatory cells as measured by flow cytometry, qRT-PCR and confocal microscopy. We also found that prior BCG vaccination restored the immunosuppressive function of T-regulatory cells of Mtb-infected T2DM mice and reduced inflammation. IL-13 producing T-regulatory cells of BCG vaccinated Mtb-infected T2DM mice converted proinflammatory M1 macrophages (iNOS) to anti-inflammatory M2 macrophage (Arg1) phenotype to suppress the inflammation. In contrast, anti-IL-13R antibody inhibited the conversion of macrophages from M1 to the M2 phenotype and enhanced the inflammatory cytokines (IL-6 and TNF-α) production. Our findings suggest a novel role for BCG in preventing excessive inflammation and mortality in T2DM mice infected with Mtb.

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Gao, Lian-Yong, Melissa Pak, Rabab Kish, Kimberly Kajihara i Eric J. Brown. "A Mycobacterial Operon Essential for Virulence In Vivo and Invasion and Intracellular Persistence in Macrophages". Infection and Immunity 74, nr 3 (marzec 2006): 1757–67. http://dx.doi.org/10.1128/iai.74.3.1757-1767.2006.

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ABSTRACT The ability to invade and grow in macrophages is necessary for Mycobacterium tuberculosis to cause disease. We have found a Mycobacterium marinum locus of two genes that is required for both invasion and intracellular survival in macrophages. The genes were designated iipA (mycobacterial invasion and intracellular persistence) and iipB. The iip mutant, which was created by insertion of a kanamycin resistance gene cassette at the 5′ region of iipA, was completely avirulent to zebra fish. Expression of the M. tuberculosis orthologue of iipA, Rv1477, fully complemented the iip mutant for infectivity in vivo, as well as for invasion and intracellular persistence in macrophages. In contrast, the iipB orthologue, Rv1478, only partially complemented the iip mutant in vivo and restored invasion but not intracellular growth in macrophages. While IipA and IipB differ at their N termini, they are highly similar throughout their C-terminal NLPC_p60 domains. The p60 domain of Rv1478 is fully functional to replace that of Rv1477, suggesting that the N-terminal sequence of Rv1477 is required for full virulence in vivo and in macrophages. Further mutations demonstrated that both Arg-Gly-Asp (RGD) and Asp-Cys-Ser-Gly (DCSG) sequences in the p60 domain are required for function. The iip mutant exhibited increased susceptibility to antibiotics and lysozyme and failed to fully separate daughter cells in liquid culture, suggesting a role for iip genes in cell wall structure and function. Altogether, these studies demonstrate an essential role for a p60-containing protein, IipA, in the pathogenesis of M. marinum infection.

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Shepard, William, Ahmed Haouz, Martin Graña, Alejandro Buschiazzo, Jean-Michel Betton, Stewart T. Cole i Pedro M. Alzari. "The Crystal Structure of Rv0813c from Mycobacterium tuberculosis Reveals a New Family of Fatty Acid-Binding Protein-Like Proteins in Bacteria". Journal of Bacteriology 189, nr 5 (15.12.2006): 1899–904. http://dx.doi.org/10.1128/jb.01435-06.

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ABSTRACT The gene Rv0813c from Mycobacterium tuberculosis, which codes for a hypothetical protein of unknown function, is conserved within the order Actinomycetales but absent elsewhere. The crystal structure of Rv0813c reveals a new family of proteins that resemble the fatty acid-binding proteins (FABPs) found in eukaryotes. Rv0813c adopts the 10-stranded β-barrel fold typical of FABPs but lacks the double-helix insert that covers the entry to the binding site in the eukaryotic proteins. The barrel encloses a deep cavity, at the bottom of which a small cyclic ligand was found to bind to the hydroxyl group of Tyr192. This residue is part of a conserved Arg-X-Tyr motif much like the triad that binds the carboxylate group of fatty acids in FABPs. Most of the residues forming the internal surface of the cavity are conserved in homologous protein sequences found in CG-rich prokaryotes, strongly suggesting that Rv0813c is a member of a new family of bacterial FABP-like proteins that may have roles in the recognition, transport, and/or storage of small molecules in the bacterial cytosol.

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van Doorn, H. R., E. J. Kuijper, A. van der Ende, A. G. A. Welten, D. van Soolingen, P. E. W. de Haas i J. Dankert. "The Susceptibility of Mycobacterium tuberculosis to Isoniazid and the Arg Leu Mutation at Codon 463 of katG Are Not Associated". Journal of Clinical Microbiology 39, nr 4 (1.04.2001): 1591–94. http://dx.doi.org/10.1128/jcm.39.4.1591-1594.2001.

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Isakova, G. T., O. A. Pak, A. U. Yusupova, Z. A. Goncharova, A. F. Tumashova, M. D. Kozhomkulov, D. K. Kozhomkulov i in. "Molecular and epidemiological characterization of rpoB mutations in rifampicin-resistant Mycobacterium tuberculosis in Kyrgyz Republic". PULMONOLOGIYA, nr 2 (28.04.2007): 44–48. http://dx.doi.org/10.18093/0869-0189-2007-0-2-44-48.

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The nature and frequency of mutations in the rpoB gene of M. tuberculosis (MBT) vary considerably in various geographical locations. There is no information on the prevalence of specific mutations in the rpoB gene of MBT isolated from patients in Kyrgyz Republic. In this work, we analyzed a distribution of the rpoB gene mutations in Kyrgyz Republic. A total of 380 rifampicin-sensitive and 225 rifampicin-resistant MBT cultures were analyzed to identify and to characterize mutations in the rpoB gene using a biological microchip assay. The biochip test determined 18 different mutation types in 8 codons of the rifampicin-resistant samples. The majority of mutations (180 of 225, or 80 %) were in the codons 531 and 526, mainly in the codon 531 (137 of 225, 60.8 %). The Ser531>Leu mutation (134 of 225, 59.4 %) was by far the most common. Another group of mutations were in the codon 526 (43 of 225, 19.1 %). Five different types of mutations were found in the codon 526 which were: His526®Tyr (4.9 %), His 526®Asp (4.9 %), His526®Arg (4.0 %), His526®Leu (3.5 %), and His526®Pro (1.8 %). The third group of common mutations were Leu511®Pro (6.3 %) and Asp516®Tyr (4.4 %). Other mutations found in the codons 533, 522, 513, and 512 were less frequent and had a very low rate comprising about 1.8 % of the total mutation number among 225 rifampicinresistant samples.

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Togre, Namdev S., Ana M. Vargas, Gunapati Bhargavi, Mohan Krishna Mallakuntla i Sangeeta Tiwari. "Fragment-Based Drug Discovery against Mycobacteria: The Success and Challenges". International Journal of Molecular Sciences 23, nr 18 (14.09.2022): 10669. http://dx.doi.org/10.3390/ijms231810669.

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The emergence of drug-resistant mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), poses an increasing global threat that urgently demands the development of new potent anti-mycobacterial drugs. One of the approaches toward the identification of new drugs is fragment-based drug discovery (FBDD), which is the most ingenious among other drug discovery models, such as structure-based drug design (SBDD) and high-throughput screening. Specialized techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and many others, are part of the drug discovery approach to combat the Mtb and NTM global menaces. Moreover, the primary drawbacks of traditional methods, such as the limited measurement of biomolecular toxicity and uncertain bioavailability evaluation, are successfully overcome by the FBDD approach. The current review focuses on the recognition of fragment-based drug discovery as a popular approach using virtual, computational, and biophysical methods to identify potent fragment molecules. FBDD focuses on designing optimal inhibitors against potential therapeutic targets of NTM and Mtb (PurC, ArgB, MmpL3, and TrmD). Additionally, we have elaborated on the challenges associated with the FBDD approach in the identification and development of novel compounds. Insights into the applications and overcoming the challenges of FBDD approaches will aid in the identification of potential therapeutic compounds to treat drug-sensitive and drug-resistant NTMs and Mtb infections.

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Burat, Bastien, Audrey Reynaerts, Dominique Baiwir, Maximilien Fléron, Sophie Gohy, Gauthier Eppe, Teresinha Leal i Gabriel Mazzucchelli. "Sweat Proteomics in Cystic Fibrosis: Discovering Companion Biomarkers for Precision Medicine and Therapeutic Development". Cells 11, nr 15 (31.07.2022): 2358. http://dx.doi.org/10.3390/cells11152358.

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In clinical routine, the diagnosis of cystic fibrosis (CF) is still challenging regardless of international consensus on diagnosis guidelines and tests. For decades, the classical Gibson and Cooke test measuring sweat chloride concentration has been a keystone, yet, it may provide normal or equivocal results. As of now, despite the combination of sweat testing, CFTR genotyping, and CFTR functional testing, a small fraction (1–2%) of inconclusive diagnoses are reported and justifies the search for new CF biomarkers. More importantly, in the context of precision medicine, with a view to early diagnosis, better prognosis, appropriate clinical follow-up, and new therapeutic development, discovering companion biomarkers of CF severity and phenotypic rescue are of utmost interest. To date, previous sweat proteomic studies have already documented disease-specific variations of sweat proteins (e.g., in schizophrenia and tuberculosis). In the current study, sweat samples from 28 healthy control subjects and 14 patients with CF were analyzed by nanoUHPLC-Q-Orbitrap-based shotgun proteomics, to look for CF-associated changes in sweat protein composition and abundance. A total of 1057 proteins were identified and quantified at an individual level, by a shotgun label-free approach. Notwithstanding similar proteome composition, enrichment, and functional annotations, control and CF samples featured distinct quantitative proteome profiles significantly correlated with CF, accounting for the respective inter-individual variabilities of control and CF sweat. All in all: (i) 402 sweat proteins were differentially abundant between controls and patients with CF, (ii) 68 proteins varied in abundance between F508del homozygous patients and patients with another genotype, (iii) 71 proteins were differentially abundant according to the pancreatic function, and iv) 54 proteins changed in abundance depending on the lung function. The functional annotation of pathophysiological biomarkers highlighted eccrine gland cell perturbations in: (i) protein biosynthesis and trafficking, (ii) CFTR proteostasis and membrane stability, and (iii) cell-cell adherence, membrane integrity, and cytoskeleton crosstalk. Cytoskeleton-related biomarkers were of utmost interest because of the consistency between variations observed here in CF sweat and variations previously documented in other CF tissues. From a clinical stance, nine candidate biomarkers of CF diagnosis (CUTA, ARG1, EZR, AGA, FLNA, MAN1A1, MIA3, LFNG, SIAE) and seven candidate biomarkers of CF severity (ARG1, GPT, MDH2, EML4 (F508del homozygous), MGAT1 (pancreatic insufficiency), IGJ, TOLLIP (lung function impairment)) were deemed suitable for further verification.

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Zhou, Xiaohong, Zhiyong Lou, Sheng Fu, Anqi Yang, Hongbo Shen, Zexuan Li, Yingji Feng, Mark Bartlam, Honghai Wang i Zihe Rao. "Crystal Structure of ArgP from Mycobacterium tuberculosis Confirms Two Distinct Conformations of Full-length LysR Transcriptional Regulators and Reveals Its Function in DNA Binding and Transcriptional Regulation". Journal of Molecular Biology 396, nr 4 (marzec 2010): 1012–24. http://dx.doi.org/10.1016/j.jmb.2009.12.033.

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Arsentieva, N. A., A. V. Semenov, D. A. Zhebrun, E. V. Vasilyeva i Areg A. Totolian. "ROLE OF CXCR3 CHEMOKINE RECEPTOR AND ITS LIGANDS IN CERTAIN DISEASES". Medical Immunology (Russia) 21, nr 4 (29.10.2019): 617–32. http://dx.doi.org/10.15789/1563-0625-2019-4-617-632.

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Chemokines are a special family of cytokines whose main function is to control cell migration; they are key players in the innate and adaptive immune responses. Directed chemotaxis of specific leukocyte subpopulations is necessary not only to maintain homeostasis, but also in development of some immunopathological conditions such as cancer, inflammation, infection, allergies and autoimmune disorders. Chemokines are pleiotropic molecules that are involved in physiological and pathophysiological processes. For example, the CXCR3 chemokine receptor is expressed on various cells: activated T and B lymphocytes, natural killers, eosinophils and neutrophils, dendritic cells, fibroblasts, endothelial and epithelial cells. Hence, CXCR3 and its ligands have a wide range of functional activity. CXCR3 ligands are the IFNγ-induced chemokines: CXCL9, CXCL10, CXCL11, and platelet-derived chemokines: CXCL4, CXCL4L1. All the CXCR3 ligands share common angiostatic properties due to lack of the Glu-Leu-Arg (ELR) motif. IFNγ-induced ligands of the CXCR3 are proinflammatory chemokines, they mainly recruit activated T cells and exert an effect on T cell polarization. Due to wide spectrum of biological activity, the ligands of CXCR3 receptor are involved in pathogenesis of various disorders, such as inflammation, infection, cancer, allergies and autoimmune disorders. In this review, we discuss the role of CXCR3 ligands in immunopathogenesis of various diseases, including the results of our studies in chronic hepatitis C, rheumatoid arthritis and pulmonary tuberculosis. Moreover, we have also discussed the potential laboratory diagnostic applicability of the chemokines in various diseases. This review illustrates a universal role of IFNγ-induced chemokines as mediators of immune responses in various diseases. The studies of CXCR3 ligands, their isoforms and receptors, interactions between themselves and with their receptors can provide a significant contribution to our understanding of the chemokine network. Understanding the system of IFNγ-dependent chemokines may have clinical implications, both for diagnostic tasks, and for therapeutic purposes.

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Guillemin, Isabelle, Vincent Jarlier i Emmanuelle Cambau. "Correlation between Quinolone Susceptibility Patterns and Sequences in the A and B Subunits of DNA Gyrase in Mycobacteria". Antimicrobial Agents and Chemotherapy 42, nr 8 (1.08.1998): 2084–88. http://dx.doi.org/10.1128/aac.42.8.2084.

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ABSTRACT The in vitro activities of seven quinolones and the sequences of the quinolone resistance-determining regions (QRDR) in the A and B subunits of DNA gyrase were determined for 14 mycobacterial species. On the basis of quinolone activity, quinolones were arranged from that with the greatest to that with the least activity as follows: sparfloxacin, levofloxacin, ciprofloxacin, ofloxacin, pefloxacin, flumequine, and nalidixic acid. Based on MICs, the species could be organized into three groups: resistant (Mycobacterium avium, M. intracellulare, M. marinum,M. chelonae, M. abscessus [ofloxacin MICs, ≥8 μg/ml]), moderately susceptible (M. tuberculosis,M. bovis BCG, M. kansasii, M. leprae, M. fortuitum third biovariant, M. smegmatis [ofloxacin MICs, 0.5 to 1 μg/ml]), and susceptible (M. fortuitum, M. peregrinum, M. aurum [ofloxacin MICs, ≤0.25 μg/ml]). Peptide sequences of the QRDR of GyrB were identical in all the species, including the amino acids at the three positions known to be involved in acquired resistance to quinolone, i.e., 426 (Asp), 447 (Arg), and 464 (Asn) (numbering system used for Escherichia coli). The last two residues could be involved in the overall low level of susceptibility of mycobacteria to quinolones since they differ from those found in the very susceptible E. coli (Lys-447 and Ser-464) but are identical to those found in the less susceptible Staphylococcus aureus and Streptococcus pneumoniae. Peptide sequences of the QRDR of GyrA were identical in all the species, except for the amino acid at position 83, which was an alanine in the two less susceptible groups and a serine in the most susceptible one, as inE. coli, suggesting that this amino acid is involved in the observed differences of quinolone susceptibility within theMycobacterium genus.

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Sakai, Tatsunori, Masao Matsuoka, Manabu Aoki, Kisato Nosaka i Hiroaki Mitsuya. "Missense mutation of the interleukin-12 receptor β1 chain–encoding gene is associated with impaired immunity againstMycobacterium avium complex infection". Blood 97, nr 9 (1.05.2001): 2688–94. http://dx.doi.org/10.1182/blood.v97.9.2688.

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Abstract Interleukin-12 (IL-12) plays an important role in the production of interferon gamma (IFN-γ) and is essential for protection against intracellular pathogens such as Mycobacterium andSalmonella. A 31-year-old man had disseminatedMycobacterium avium complex (MAC) infection. The production of IFN-γ by peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA-PBMCs) was found severely impaired (40.7 pg/mL compared with 833 ± 289 pg/mL for the patient's and healthy subjects' (n = 3) PHA- PBMCs, respectively), and the patient's PHA-PBMCs completely lacked surface IL-12 receptor β1 (IL-12Rβ1) chain. The IL-12Rβ1 gene transcript in his PHA-PBMCs had an R213W substitution in each allele. Family history showed that both parents were heterozygotes in the R213W substitution. Transfection of a human embryonal kidney cell line 293 (HEKC293) with wild-type IL-12Rβ1wt gene led to cell surface IL-12Rβ1 expression; however, no expression was seen in HEKC293 transfected with the mutated IL-12Rβ1R213W gene. TheIL-12Rβ1 gene transcript, but no IL-12Rβ1 protein, was detected in PHA-PBMCs and T cells, suggesting a post-translational event(s), most likely a shortened turnover of the protein. The R213W substitution was not detected in the cells of 32 healthy persons or of 25 patients with tuberculosis or MAC infection. Six amino acid substitutions (Q214R, M365T, G378R, H438Y, A525T, and G594E) were identified, but the incidences of such substitutions were not significantly different between the groups. The Q214R substitution is reportedly linked to IL-12Rβ1 deficiency; however, the study showed that 19 and 10 of 57 Japanese and 6 and 4 of 33 healthy white persons were heterozygous and homozygous for Arg-214, respectively, suggesting that the Q214R substitution represents a polymorphism and is not related to IL-12Rβ1 deficiency but that the R213W substitution is responsible for IL-12Rβ1 deficiency.

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Lu, Chung-Dar, i Ahmed T. Abdelal. "The gdhB Gene of Pseudomonas aeruginosaEncodes an Arginine-Inducible NAD+-Dependent Glutamate Dehydrogenase Which Is Subject to Allosteric Regulation". Journal of Bacteriology 183, nr 2 (15.01.2001): 490–99. http://dx.doi.org/10.1128/jb.183.2.490-499.2001.

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ABSTRACT The NAD+-dependent glutamate dehydrogenase (NAD-GDH) from Pseudomonas aeruginosa PAO1 was purified, and its amino-terminal amino acid sequence was determined. This sequence information was used in identifying and cloning the encodinggdhB gene and its flanking regions. The molecular mass predicted from the derived sequence for the encoded NAD-GDH was 182.6 kDa, in close agreement with that determined from sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified enzyme (180 kDa). Cross-linking studies established that the native NAD-GDH is a tetramer of equal subunits. Comparison of the derived amino acid sequence of NAD-GDH from P. aeruginosa with the GenBank database showed the highest homology with hypothetical polypeptides from Pseudomonas putida, Mycobacterium tuberculosis, Rickettsia prowazakii, Legionella pneumophila, Vibrio cholerae, Shewanella putrefaciens, Sinorhizobium meliloti, andCaulobacter crescentus. A moderate degree of homology, primarily in the central domain, was observed with the smaller tetrameric NAD-GDH (protomeric mass of 110 kDa) fromSaccharomyces cerevisiae or Neurospora crassa. Comparison with the yet smaller hexameric GDH (protomeric mass of 48 to 55 kDa) of other prokaryotes yielded a low degree of homology that was limited to residues important for binding of substrates and for catalytic function. NAD-GDH was induced 27-fold by exogenous arginine and only 3-fold by exogenous glutamate. Primer extension experiments established that transcription of gdhB is initiated from an arginine-inducible promoter and that this induction is dependent on the arginine regulatory protein, ArgR, a member of the AraC/XyIS family of regulatory proteins. NAD-GDH was purified to homogeneity from a recombinant strain of P. aeruginosa and characterized. The glutamate saturation curve was sigmoid, indicating positive cooperativity in the binding of glutamate. NAD-GDH activity was subject to allosteric control by arginine and citrate, which function as positive and negative effectors, respectively. Both effectors act by influencing the affinity of the enzyme for glutamate. NAD-GDH from this organism differs from previously characterized enzymes with respect to structure, protomer mass, and allosteric properties indicate that this enzyme represents a novel class of microbial glutamate dehydrogenases.

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Mishra, Archita, Ashalatha S. Mamidi, Raju S. Rajmani, Ananya Ray, Rajanya Roy i Avadhesha Surolia. "An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy". EMBO Molecular Medicine 10, nr 4 (26.02.2018). http://dx.doi.org/10.15252/emmm.201708038.

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Mishra, Archita, Ashalatha S. Mamidi, Raju S. Rajmani, Ananya Ray, Rajanya Roy i Avadhesha Surolia. "An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy". EMBO Molecular Medicine 11, nr 10 (październik 2019). http://dx.doi.org/10.15252/emmm.201911209.

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Alcock, Brian P., William Huynh, Romeo Chalil, Keaton W. Smith, Amogelang R. Raphenya, Mateusz A. Wlodarski, Arman Edalatmand i in. "CARD 2023: expanded curation, support for machine learning, and resistome prediction at the Comprehensive Antibiotic Resistance Database". Nucleic Acids Research, 20.10.2022. http://dx.doi.org/10.1093/nar/gkac920.

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Abstract The Comprehensive Antibiotic Resistance Database (CARD; card.mcmaster.ca) combines the Antibiotic Resistance Ontology (ARO) with curated AMR gene (ARG) sequences and resistance-conferring mutations to provide an informatics framework for annotation and interpretation of resistomes. As of version 3.2.4, CARD encompasses 6627 ontology terms, 5010 reference sequences, 1933 mutations, 3004 publications, and 5057 AMR detection models that can be used by the accompanying Resistance Gene Identifier (RGI) software to annotate genomic or metagenomic sequences. Focused curation enhancements since 2020 include expanded β-lactamase curation, incorporation of likelihood-based AMR mutations for Mycobacterium tuberculosis, addition of disinfectants and antiseptics plus their associated ARGs, and systematic curation of resistance-modifying agents. This expanded curation includes 180 new AMR gene families, 15 new drug classes, 1 new resistance mechanism, and two new ontological relationships: evolutionary_variant_of and is_small_molecule_inhibitor. In silico prediction of resistomes and prevalence statistics of ARGs has been expanded to 377 pathogens, 21,079 chromosomes, 2,662 genomic islands, 41,828 plasmids and 155,606 whole-genome shotgun assemblies, resulting in collation of 322,710 unique ARG allele sequences. New features include the CARD:Live collection of community submitted isolate resistome data and the introduction of standardized 15 character CARD Short Names for ARGs to support machine learning efforts.

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Elamurugan, TP. "Primary Pancreatic Tuberculosis: A Rare Case Report". Advanced Research in Gastroenterology & Hepatology 13, nr 2 (14.06.2019). http://dx.doi.org/10.19080/argh.2019.13.555858.

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Khalil, Zeinab G., Timothy A. Hill, Luis M. De Leon Rodriguez, Rink-Jan Lohman, Huy N. Hoang, Norbert Reiling, Doris Hillemann i in. "Structure-Activity Relationships of Wollamide Cyclic Hexapeptides with Activity against Drug-Resistant and Intracellular Mycobacterium tuberculosis". Antimicrobial Agents and Chemotherapy 63, nr 3 (2.01.2019). http://dx.doi.org/10.1128/aac.01773-18.

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ABSTRACT Wollamides are cyclic hexapeptides, recently isolated from an Australian soil Streptomyces isolate, that exhibit promising in vitro antimycobacterial activity against Mycobacterium bovis Bacille Calmette Guérin without displaying cytotoxicity against a panel of mammalian cells. Here, we report the synthesis and antimycobacterial activity of 36 new synthetic wollamides, collated with all known synthetic and natural wollamides, to reveal structure characteristics responsible for in vitro growth-inhibitory activity against Mycobacterium tuberculosis (H37Rv, H37Ra, CDC1551, HN878, and HN353). The most potent antimycobacterial wollamides were those where residue VI d-Orn (wollamide B) was replaced by d-Arg (wollamide B1) or d-Lys (wollamide B2), with all activity being lost when residue VI was replaced by Gly, l-Arg, or l-Lys (wollamide B3). Substitution of other amino acid residues mainly reduced or ablated antimycobacterial activity. Significantly, whereas wollamide B2 was the most potent in restricting M. tuberculosis in vitro, wollamide B1 restricted M. tuberculosis intracellular burden in infected macrophages. Wollamide B1 synergized with pretomanid (PA-824) in inhibiting M. tuberculosis in vitro growth but did not antagonize prominent first- and second-line tuberculosis antibiotics. Furthermore, wollamide B1 exerted bactericidal activity against nonreplicating M. tuberculosis and impaired growth of multidrug- and extensively drug-resistant clinical isolates. In vivo pharmacokinetic profiles for wollamide B1 in rats and mice encourage further optimization of the wollamide pharmacophore for in vivo bioavailability. Collectively, these observations highlight the potential of the wollamide antimycobacterial pharmacophore.

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Brenner, Evan P., i Srinand Sreevatsan. "Attenuated but immunostimulatory Mycobacterium tuberculosis variant bovis strain Ravenel shows variation in T cell epitopes". Scientific Reports 13, nr 1 (31.07.2023). http://dx.doi.org/10.1038/s41598-023-39578-5.

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AbstractTuberculosis, caused by Mycobacterium tuberculosis complex (MTBC) organisms, affects a range of humans and animals globally. Mycobacterial pathogenesis involves manipulation of the host immune system, partially through antigen presentation. Epitope sequences across the MTBC are evolutionarily hyperconserved, suggesting their recognition is advantageous for the bacterium. Mycobacterium tuberculosis var. bovis (MBO) strain Ravenel is an isolate known to provoke a robust immune response in cattle, but typically fails to produce lesions and persist. Unlike attenuated MBO BCG strains that lack the critical RD1 genomic region, Ravenel is classic-type MBO structurally, suggesting genetic variation is responsible for defective pathogenesis. This work explores variation in epitope sequences in MBO Ravenel by whole genome sequencing, and contrasts such variation against a fully virulent clinical isolate, MBO strain 10-7428. Validated MTBC epitopes (n = 4818) from the Immune Epitope Database were compared to their sequences in MBO Ravenel and MBO 10-7428. Ravenel yielded 3 modified T cell epitopes, in genes rpfB, argC, and rpoA. These modifications were predicted to have little effect on protein stability. In contrast, T cells epitopes in 10-7428 were all WT. Considering T cell epitope hyperconservation across MTBC variants, these altered MBO Ravenel epitopes support their potential contribution to overall strain attenuation. The affected genes may provide clues on basic pathogenesis, and if so, be feasible targets for reverse vaccinology.

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Smrt, Sean T., Cristian A. Escobar, Souvik Dey, Timothy A. Cross i Huan-Xiang Zhou. "An Arg/Ala-rich helix in the N-terminal region of M. tuberculosis FtsQ is a potential membrane anchor of the Z-ring". Communications Biology 6, nr 1 (23.03.2023). http://dx.doi.org/10.1038/s42003-023-04686-5.

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AbstractMtb infects a quarter of the worldwide population. Most drugs for treating tuberculosis target cell growth and division. With rising drug resistance, it becomes ever more urgent to better understand Mtb cell division. This process begins with the formation of the Z-ring via polymerization of FtsZ and anchoring of the Z-ring to the inner membrane. Here we show that the transmembrane protein FtsQ is a potential membrane anchor of the Mtb Z-ring. In the otherwise disordered cytoplasmic region of FtsQ, a 29-residue, Arg/Ala-rich α-helix is formed that interacts with upstream acidic residues in solution and with acidic lipids at the membrane surface. This helix also binds to the GTPase domain of FtsZ, with implications for drug binding and Z-ring formation.

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Gliddon, Harriet D., Myrsini Kaforou, Mary Alikian, Dominic Habgood-Coote, Chenxi Zhou, Tolu Oni, Suzanne T. Anderson i in. "Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification". Frontiers in Immunology 12 (2.03.2021). http://dx.doi.org/10.3389/fimmu.2021.637164.

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Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate diagnostic test development. To identify minimal transcript signatures, we applied a transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were further investigated using reverse transcriptase (RT)—digital PCR (dPCR). A four-transcript signature (GBP6, TMCC1, PRDM1, and ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2–100%). A three-transcript signature (FCGR1A, ZNF296, and C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3–100%), regardless of HIV. These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.

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Barreto Alves, Jose Antonio, Mariangela da Silva Nunes, Ricardo Fakhouri, Paulo Ricardo Saquete Martins-Filho, Maria do Carmo de Oliveira Ribeiro, Alberto Correa de Vasconcellos, Patricia Oliveira Santos i in. "Inhibition of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains by essential oil from Croton argyrophylloides Mull. Arg." International Archives of Medicine, 2016. http://dx.doi.org/10.3823/2047.

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Khan, Masood Alam. "Targeted Drug Delivery Using Tuftsin-bearing Liposomes: Implications in the treatment of infectious diseases and tumors". Current Drug Targets 21 (25.11.2020). http://dx.doi.org/10.2174/1389450121999201125200756.

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Abstract:: Tuftsin, a tetrapeptide (Thr-Lys-Pro-Arg), acts as an immunopotentiating molecule with its ability to bind and activate many immune cells, including macrophages or monocytes, neutrophils and dendritic cells. The specific targeting activity of tuftsin has been further increased by its palmitoylation followed by its incorporation into the lipid bilayer of liposomes. Tuftsin-bearing liposomes (Tuft-liposomes) possess several characteristics that enable them to act as a potential drug and vaccine carriers. Tuft-liposomes-loaded anti-microbial drugs have been shown to be highly effective against many infectious diseases, including tuberculosis, leishmaniasis, malaria, candidiasis, cryptococosis. Moreover, Tuft-liposomes also increased the activity of anticancer drug etoposide against fibrosarcoma in mice. Tuft-liposomes showed the immune-potentiating effect and rejuvenated the immune cells in the leukopenic mice. In addition, antigens encapsulated in Tuftsin-bearing liposomes demonstrated greater immunogenicity by increasing the T cell proliferation and antibody secretion. Keep-ing into consideration of their specific targeting and immunopotentiating effects, Tuft-liposomes may potentially be used as promising drug and vaccine delivery systems.

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Viswanath, I. V. Kasi, Ganji Sreekanth Reddy, Anna Venkateswara Rao, M. S. N. A. Prasad i Eppakayala Laxminarayana. "Some new 1,2,4–triazole derivatives bearing the pyrimidine moiety as potential antimycobacterial agents: Synthesis and docking analysis". Letters in Drug Design & Discovery 19 (29.08.2022). http://dx.doi.org/10.2174/1570180819666220829143739.

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Background: Pyrimidine and 1,2,4–triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericide, fungicides, vermicide, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: A novel set of heterocyclic derivatives comprising 1,2,4–triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity. Methods: In this study, we performed ligand–based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl–pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti–TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain. Results: Our results revealed that the target 1,2,4–triazoles 7d, 7e, 7c have potent potency against Gram–(+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 µg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram–(–ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 µg/mL). Among all tested compounds, 7a, 7e, 7h revealed an outstanding antitubercular activity against M. tuberculosis H37RV strain with MICs of 3.24, 8.93, and 4.70 µg/mL respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 A˚], LysA:103 [3.103, 2.164 A˚], GlyA:102 [1.713 A˚], ArgA:238 [1.713 A˚], ValA:101 [2.113 A˚] (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 A˚] [Pi-Pi] respectively. Conclusion: In this communication, our aim has been veriﬁed by the synthesis of 3-methoxy-10,12-dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4–triazole and pyrimidine moieties with benzoxepine in a single molecular framework. After all above ﬁndings it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.

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