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https://www.readbyqxmd.com/read/30332914/the-systematic-modeling-studies-and-free-energy-calculations-of-the-phenazine-compounds-as-anti-tuberculosis-agents
#1
Yueqi Wang, Abbas Khan, Aman Chandra Kaushik, Muhammad Junaid, Xuehong Zhang, Dong-Qing Wei
Phenazine compounds have good activity against Mycobacterium tuberculosis. Based on the reported activities that were obtained in Mycobacterium tuberculosis H37Rv, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was built to design novel compounds against MTB. A 5-fold cross-validation method and external validation were used to analyze the accuracy of forecasting. The model has a cross-validation coefficient q2 =0.7 and a non-cross-validation coefficient r2 =0.903, indicating that the model has good predictive possibility...
October 17, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/30324906/maturing-mycobacterium-smegmatis-peptidoglycan-requires-non-canonical-crosslinks-to-maintain-shape
#2
Catherine Baranowski, Michael A Welsh, Lok-To Sham, Haig A Eskandarian, Hoong C Lim, Karen J Kieser, Jeffrey C Wagner, John McKinney, Georg E Fantner, Thomas R Ioerger, Suzanne Walker, Thomas G Bernhardt, Eric J Rubin, E Hesper Rego
In most well studied rod-shaped bacteria, peptidoglycan is primarily crosslinked by penicillin-binding proteins (PBPs). However, in mycobacteria, crosslinks formed by L,D-transpeptidases (LDTs) are highly abundant. To elucidate the role of these unusual crosslinks, we characterized Mycobacterium smegmatis cells lacking all LDTs. We find that crosslinks generate by LDTs are required for rod shape maintenance specifically at sites of aging cell wall, a byproduct of polar elongation. Asymmetric polar growth leads to a non-uniform distribution of these two types of crosslinks in a single cell...
October 16, 2018: ELife
https://www.readbyqxmd.com/read/30322337/autophagy-a-new-strategy-for-host-directed-therapy-of-tuberculosis
#3
Seungwha Paik, Jin Kyung Kim, Chaeuk Chung, Eun-Kyeong Jo
Tuberculosis (TB), which is primarily caused by the major etiologic agent Mycobacterium tuberculosis (Mtb), remains a serious infectious disease worldwide. Recently, much effort has been made to develop novel/improved therapies by modulating host responses to TB (i.e., host-directed therapy). Autophagy is an intracellular catabolic process that helps maintain homeostasis or the removal of invading pathogens via a lysosomal degradation process. The activation of autophagy by diverse drugs or agents may represent a promising treatment strategy against Mtb infection, even to drug-resistant strains...
October 15, 2018: Virulence
https://www.readbyqxmd.com/read/30319771/a-gfp-strategy-for-efficient-recombinant-protein-overexpression-and-purification-in-mycobacterium-smegmatis
#4
Anjana Radhakrishnan, Christopher M Furze, Mohd Syed Ahangar, Elizabeth Fullam
One of the major obstacles to obtaining a complete structural and functional understanding of proteins encoded by the Mycobacterium tuberculosis ( Mtb ) pathogen is due to significant difficulties in producing recombinant mycobacterial proteins. Recent advances that have utilised the closely related Mycobacterium smegmatis species as a native host have been effective. Here we have developed a method for the rapid screening of both protein production and purification strategies of mycobacterial proteins in whole M...
September 27, 2018: RSC Advances
https://www.readbyqxmd.com/read/30318462/a-lysine-acetyltransferase-contributes-to-the-metabolic-adaptation-to-hypoxia-in-mycobacterium-tuberculosis
#5
Emily S C Rittershaus, Seung-Hun Baek, Inna V Krieger, Samantha J Nelson, Yu-Shan Cheng, Subhalaxmi Nambi, Richard E Baker, John D Leszyk, Scott A Shaffer, James C Sacchettini, Christopher M Sassetti
Upon inhibition of respiration, which occurs in hypoxic or nitric oxide-containing host microenvironments, Mycobacterium tuberculosis (Mtb) adopts a non-replicating "quiescent" state and becomes relatively unresponsive to antibiotic treatment. We used comprehensive mutant fitness analysis to identify regulatory and metabolic pathways that are essential for the survival of quiescent Mtb. This genetic study identified a protein acetyltransferase (Mt-Pat/Rv0998) that promoted survival and altered the flux of carbon from oxidative to reductive tricarboxylic acid (TCA) reactions...
October 4, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/30301350/compound-molecular-logic-in-accessing-the-active-site-of-m-tuberculosis-protein-tyrosine-phosphatase-b
#6
Thomas E Morrell, Ilona Urszula Rafalska-Metcalf, Haw Yang, Jhih-Wei Chu
Protein tyrosine phosphatase B (PtpB) from Mycobacterium tuberculosis (Mtb) extends the bacteria's survival in hosts and hence is a potential target for Mtb-specific drugs. To study how Mtb-specific sequence insertions in PtpB may regulate access to its active site through large-amplitude conformational changes, we performed free-energy calculations using an all-atom explicit solvent model. Corroborated by biochemical assays, the results show that PtpB's active site is controlled via an "either/or" compound conformational gating mechanism---an unexpected discovery that Mtb has evolved to bestow a single enzyme with such intricate logical operations...
October 10, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/30281201/global-profiling-of-pkng-interactions-using-a-human-proteome-microarray-reveals-novel-connections-with-cypa
#7
Fan-Lin Wu, Yin Liu, Hai-Nan Zhang, He-Wei Jiang, Li Cheng, Shu-Juan Guo, Jiao-Yu Deng, Li-Jun Bi, Xian-En Zhang, Hua-Fang Gao, Sheng-Ce Tao
Mycobacterium tuberculosis (Mtb) serine/threonine kinase PknG plays an important role in the Mtb-host interaction by facilitating the survival of Mtb in macrophages. However, the human proteins with which the PknG interacts, and the underlying molecular mechanisms are still largely unknown. In this study, we applied a HuProtTM array to globally identify the host proteins to which PknG binds. In this way, we discovered 125 interactors, including a cyclophilin protein, CypA. This interaction between PknG and CypA was validated both in vitro and in vivo, and functional studies showed that PknG significantly reduces the protein levels of CypA through phosphorylation, which consequently inhibit the inflammatory response through down-regulation of NF-κB and ERK1/2 pathways...
October 3, 2018: Proteomics
https://www.readbyqxmd.com/read/30269499/integrating-multifaceted-information-to-predict-mycobacterium-tuberculosis-human-protein-protein-interactions
#8
Jun Sun, Ling-Li Yang, Xi Chen, De-Xin Kong, Rong Liu
Tuberculosis (TB) is one of the biggest infectious disease killers caused by Mycobacterium tuberculosis (MTB). Studying the protein-protein interactions (PPIs) between MTB and human can deepen our understanding of the pathogenesis of TB and offer new clues for the treatment against MTB infection, but the experimentally validated interactions are especially scarce in this regard. Herein we proposed an integrated framework that combined template-, domain-domain interaction-, and machine learning-based methods to predict MTB-human PPIs...
October 1, 2018: Journal of Proteome Research
https://www.readbyqxmd.com/read/30267625/validation-of-mycobacterium-tuberculosis-real-time-polymerase-chain-reaction-for-diagnosis-of-tuberculous-meningitis-using-cerebrospinal-fluid-samples-a-pilot-study
#9
Sérgio M de Almeida, Conrado M Borges, Lucas B Santana, Gilberto Golin, Lísia Correa, Gislene B Kussen, Keite Nogueira
Background Timely diagnosis of tuberculous meningitis (TBM) remains challenging. Molecular diagnostic tools are necessary, particularly in low- and middle-income countries. There is no approved commercial polymerase chain reaction (PCR) assay that can be used to detect Mycobacterium tuberculosis in non-respiratory samples, such as the cerebrospinal fluid (CSF). We aimed to validate the threshold cycle (Ct) cut-off points; calculate the operational characteristics of real-time PCR for detection of M. tuberculosis (MTb qPCR) in the CSF; and the inhibitory affect of CSF red blood cells (RBC) and total proteins on MTb qPCR...
September 29, 2018: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/30258084/comparison-of-immunogenicity-and-vaccine-efficacy-between-heat-shock-proteins-hsp70-and-grpe-in-the-dnak-operon-of-mycobacterium-tuberculosis
#10
Woo Sik Kim, Jong-Seok Kim, Hong Min Kim, Kee Woong Kwon, Seok-Yong Eum, Sung Jae Shin
Antigens (Ags) in Mycobacterium tuberculosis (Mtb) that are constitutively expressed, overexpressed during growth, essential for survival, and highly conserved may be good vaccine targets if they induce the appropriate anti-Mtb Th1 immune response. In this context, stress response-related antigens of Mtb might serve as attractive targets for vaccine development as they are rapidly expressed and are up-regulated during Mtb infection in vivo. Our group recently demonstrated that GrpE, encoded by rv0351 as a cofactor of heat-shock protein 70 (HSP70) in the DnaK operon, is a novel immune activator that interacts with DCs to generate Th1-biased memory T cells in an antigen-specific manner...
September 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30257943/atp-hydrolysis-coupled-peptide-translocation-mechanism-of-mycobacterium-tuberculosis-clpb
#11
Hongjun Yu, Tania J Lupoli, Amanda Kovach, Xing Meng, Gongpu Zhao, Carl F Nathan, Huilin Li
The protein disaggregase ClpB hexamer is conserved across evolution and has two AAA+-type nucleotide-binding domains, NBD1 and NBD2, in each protomer. In M. tuberculosis ( Mtb ), ClpB facilitates asymmetric distribution of protein aggregates during cell division to help the pathogen survive and persist within the host, but a mechanistic understanding has been lacking. Here we report cryo-EM structures at 3.8- to 3.9-Å resolution of Mtb ClpB bound to a model substrate, casein, in the presence of the weakly hydrolyzable ATP mimic adenosine 5'-[γ-thio]triphosphate...
October 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/30249983/applications-of-magnetotactic-bacteria-magnetosomes-and-magnetosome-crystals-in-biotechnology-and-nanotechnology-mini-review
#12
REVIEW
Gabriele Vargas, Jefferson Cypriano, Tarcisio Correa, Pedro Leão, Dennis A Bazylinski, Fernanda Abreu
Magnetotactic bacteria (MTB) biomineralize magnetosomes, which are defined as intracellular nanocrystals of the magnetic minerals magnetite (Fe₃O₄) or greigite (Fe₃S₄) enveloped by a phospholipid bilayer membrane. The synthesis of magnetosomes is controlled by a specific set of genes that encode proteins, some of which are exclusively found in the magnetosome membrane in the cell. Over the past several decades, interest in nanoscale technology (nanotechnology) and biotechnology has increased significantly due to the development and establishment of new commercial, medical and scientific processes and applications that utilize nanomaterials, some of which are biologically derived...
September 24, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/30248156/expression-of-a-recombinant-4-phosphopantetheinylated-active-m-tuberculosis-fatty-acid-synthase-i-in-e-coli
#13
Szilvia Baron, Yoav Peleg, Jacob Grunwald, David Morgenstern, Nadav Elad, Moshe Peretz, Shira Albeck, Yishai Levin, John T Welch, Kim A DeWeerd, Alon Schwarz, Yigal Burstein, Ron Diskin, Zippora Shakked, Oren Zimhony
BACKGROUND: Fatty acid synthase 1 (FAS I) from Mycobacterium tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4'-Phosphopantetheine (4'-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4'-PP transferase, termed acyl carrier protein synthase (AcpS)...
2018: PloS One
https://www.readbyqxmd.com/read/30245472/g-quadruplex-forming-dna-aptamers-inhibit-the-dna-binding-function-of-hupb-and-mycobacteriumtuberculosis-entry-into-host-cells
#14
Priya Kalra, Subodh Kumar Mishra, Surinder Kaur, Amit Kumar, Hanumanthappa Krishna Prasad, Tarun Kumar Sharma, Jaya Sivaswami Tyagi
The entry and survival of Mycobacterium tuberculosis (Mtb) within host cells is orchestrated partly by an essential histone-like protein HupB (Rv2986c). Despite being an essential drug target, the lack of structural information has impeded the development of inhibitors targeting the indispensable and multifunctional C-terminal domain (CTD) of HupB. To bypass the requirement for structural information in the classical drug discovery route, we generated a panel of DNA aptamers against HupB protein through systemic evolution of ligands by exponential (SELEX) enrichment...
August 22, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/30242834/the-tyrosine-kinase-inhibitor-dasatinib-reduces-the-growth-of-intracellular-mycobacterium-tuberculosis-despite-impairing-t-cell-function
#15
Stephanie Wehrstedt, Jan Kubis, Andreas Zimmermann, Heiko Bruns, Daniel Mayer, Mark Grieshober, Steffen Stenger
Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abl-tyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb)...
September 22, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/30233588/pd-1-expression-on-mycobacterium-tuberculosis-specific-cd4-t-cells-is-associated-with-bacterial-load-in-human-tuberculosis
#16
Cheryl L Day, Deborah A Abrahams, Rubina Bunjun, Lynnett Stone, Marwou de Kock, Gerhard Walzl, Robert J Wilkinson, Wendy A Burgers, Willem A Hanekom
Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of Mycobacterium tuberculosis (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity of Mtb-specific T cell responses...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30232332/rv2346c-enhances-mycobacterial-survival-within-macrophages-by-inhibiting-tnf-%C3%AE-and-il-6-production-via-the-p38-mirna-nf-%C3%AE%C2%BAb-pathway
#17
Jing Yao, Xingran Du, Sixia Chen, Yan Shao, Kaili Deng, Mingzi Jiang, Jingning Liu, Ziyan Shen, Xiaolin Chen, Ganzhu Feng
The intracellular survival of Mycobacterium tuberculosis (Mtb) has a central role in the pathogenesis of tuberculosis. Mtb Rv2346c is a member of 6-kDa early secreted antigenic target family of proteins, which are known to inhibit the host immune responses to promote bacillary persistence in macrophages. However, the mechanism through which Rv2346c participates in Mtb pathogenesis is unclear. In the present study, recombinant Rv2346c protein was synthesized and used to treat Bacillus Calmette-Guérin (BCG)-infected macrophages...
September 19, 2018: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/30194101/a-method-for-genome-editing-in-the-anaerobic-magnetotactic-bacterium-desulfovibrio-magneticus-rs-1
#18
Carly R Grant, Kristen N LeGault, Lilah Rahn-Lee, Arash Komeili
Magnetosomes are complex bacterial organelles that serve as model systems for studying bacterial cell biology, biomineralization, and global iron cycling. Magnetosome biogenesis is primarily studied in two closely related Alphaproteobacteria of the genus Magnetospirillum that form cubooctahedral-shaped magnetite crystals within a lipid membrane. However, chemically and structurally distinct magnetic particles have been found in physiologically and phylogenetically diverse bacteria. Due to a lack of molecular genetic tools, the mechanistic diversity of magnetosome formation remains poorly understood...
September 7, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/30192649/yield-and-efficiency-of-novel-intensified-tuberculosis-case-finding-algorithms-for-people-living-with-hiv
#19
Christina Yoon, Fred C Semitala, Lucy Asege, Jane Katende, Sandra Mwebe, Alfred O Andama, Elly Atuhumuza, Martha Nakaye, Derek T Armstrong, David W Dowdy, Charles E McCulloch, Moses Kamya, Adithya Cattamanchi
Rationale/Objectives: The recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (PLHIV) - symptom-based screening followed by Xpert MTB/RIF (Xpert) testing - is insufficiently sensitive and results in unnecessary Xpert testing. We evaluated whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert and/or culture could improve ICF yield and efficiency. Methods/Measurements: We compared the yield and efficiency of novel ICF algorithms inclusive of POC CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count ≤100 cells/μL), sputum Xpert, and/or a single sputum culture among consecutive PLHIV with CD4 counts ≤350 cells/uL initiating antiretroviral therapy in Uganda...
September 7, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/30192424/pe_pgrs3-of-mycobacterium-tuberculosis-is-specifically-expressed-at-low-phosphate-concentration-and-its-arginine-rich-c-terminal-domain-mediates-adhesion-and-persistence-in-host-tissues-when-expressed-in-mycobacterium-smegmatis
#20
Flavio De Maio, Basem Battah, Valentina Palmieri, Linda Petrone, Francesco Corrente, Alessandro Salustri, Ivana Palucci, Silvia Bellesi, Massimiliano Papi, Salvatore Rubino, Michela Sali, Delia Goletti, Maurizio Sanguinetti, Riccardo Manganelli, Marco De Spirito, Giovanni Delogu
PE_PGRSs of Mycobacterium tuberculosis (Mtb) represent a family of complex and peculiar proteins whose role and function remain elusive. In this study, we investigated PE_PGRS3 and PE_PGRS4, two highly homologous PE_PGRSs encoded by two contiguous genes in the Mtb genome. Using a gene-reporter system in Mycobacterium smegmatis (Ms) and transcriptional analysis in Mtb, we show that PE_PGRS3, but not PE_PGRS4, is specifically expressed under low phosphate concentrations. Interestingly, PE_PGRS3, but not PE_PGRS4, has a unique, arginine-rich C-terminal domain of unknown function...
September 7, 2018: Cellular Microbiology
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