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Lipid metabolism tuberculosis

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https://www.readbyqxmd.com/read/29675017/-de-novo-fatty-acid-synthesis-during-mycobacterial-infection-is-a-prerequisite-for-the-function-of-highly-proliferative-t-cells-but-not-for-dendritic-cells-or-macrophages
#1
Philipp Stüve, Lucía Minarrieta, Hanna Erdmann, Catharina Arnold-Schrauf, Maxine Swallow, Melanie Guderian, Freyja Krull, Alexandra Hölscher, Peyman Ghorbani, Jochen Behrends, Wolf-Rainer Abraham, Christoph Hölscher, Tim D Sparwasser, Luciana Berod
Mycobacterium tuberculosis ( Mtb ), the causative agent of human tuberculosis, is able to efficiently manipulate the host immune system establishing chronic infection, yet the underlying mechanisms of immune evasion are not fully understood. Evidence suggests that this pathogen interferes with host cell lipid metabolism to ensure its persistence. Fatty acid metabolism is regulated by acetyl-CoA carboxylase (ACC) 1 and 2; both isoforms catalyze the conversion of acetyl-CoA into malonyl-CoA, but have distinct roles...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29668262/visualization-of-mycobacterial-biomarkers-and-tuberculosis-drugs-in-infected-tissue-by-maldi-ms-imaging
#2
Landry Blanc, Anne J Lenaerts, Véronique Dartois, Brendan Prideaux
MALDI mass spectrometry imaging (MALDI-MSI) is a technique capable of label-free identification and visualization of analytes in tissue sections. We have previously applied MALDI-MSI to study the spatial distribution of tuberculosis (TB) drugs in necrotic lung granulomas characteristic of pulmonary TB disease, revealing heterogeneous and often suboptimal drug distribution. To investigate the impact of differential drug distribution at the sites of infection, we sought to image mycobacterial biomarkers to co-register drugs and bacteria in lesion sections...
April 18, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/29663798/avoiding-antibiotic-inactivation-in-mycobacterium-tuberculosis-by-rv3406-through-strategic-nucleoside-modification
#3
Matthew R Bockman, Curtis A Engelhart, Surendra Dawadi, Peter Larson, Divya Tiwari, David M Ferguson, Dirk Schnappinger, Courtney C Aldrich
5'-[ N-(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis ( Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase ( MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5'-position to prevent enzymatic inactivation...
April 17, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29648787/measuring-the-global-substrate-specificity-of-mycobacterial-serine-hydrolases-using-a-library-of-fluorogenic-ester-substrates
#4
Braden Bassett, Brent Waibel, Alex White, Heather Hansen, Dominique Stephens, Andrew Koelper, Erik M Larsen, Charles Kim, Adam Glanzer, Luke D Lavis, Geoffrey C Hoops, R Jeremy Johnson
Among the proteins required for lipid metabolism in Mycobacterium tuberculosis are a significant number of uncharacterized serine hydrolases, especially lipases and esterases. Using a streamlined synthetic method, a library of immolative fluorogenic ester substrates was expanded to better represent the natural lipidomic diversity of Mycobacterium. This expanded fluorogenic library was then used to rapidly characterize the global structure activity relationship (SAR) of mycobacterial serine hydrolases in M. smegmatis under different growth conditions...
April 16, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29593722/formation-of-foamy-macrophages-by-tuberculous-pleural-effusions-is-triggered-by-the-interleukin-10-signal-transducer-and-activator-of-transcription-3-axis-through-acat-upregulation
#5
Melanie Genoula, José Luis Marín Franco, Maeva Dupont, Denise Kviatcovsky, Ayelén Milillo, Pablo Schierloh, Eduardo Jose Moraña, Susana Poggi, Domingo Palmero, Dulce Mata-Espinosa, Erika González-Domínguez, Juan Carlos León Contreras, Paula Barrionuevo, Bárbara Rearte, Marlina Olyissa Córdoba Moreno, Adriana Fontanals, Agostina Crotta Asis, Gabriela Gago, Céline Cougoule, Olivier Neyrolles, Isabelle Maridonneau-Parini, Carmen Sánchez-Torres, Rogelio Hernández-Pando, Christel Vérollet, Geanncarlo Lugo-Villarino, María Del Carmen Sasiain, Luciana Balboa
The ability of Mycobacterium tuberculosis (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29573124/the-role-of-lipids-in-host-pathogen-interactions
#6
REVIEW
Glenn F W Walpole, Sergio Grinstein, Johannes Westman
Innate immunity relies on the effective recognition and elimination of pathogenic microorganisms. This entails sequestration of pathogens into phagosomes that promptly acquire microbicidal and degradative properties. This complex series of events, which involve cytoskeletal reorganization, membrane remodeling and the activation of multiple enzymes, is orchestrated by lipid signaling. To overcome this immune response, intracellular pathogens acquired mechanisms to subvert phosphoinositide-mediated signaling and use host lipids, notably cholesterol, as nutrients...
March 23, 2018: IUBMB Life
https://www.readbyqxmd.com/read/29524441/modelling-the-effects-of-bacterial-cell-state-and-spatial-location-on-tuberculosis-treatment-insights-from-a-hybrid-multiscale-cellular-automaton-model
#7
Ruth Bowness, Mark A J Chaplain, Gibin G Powathil, Stephen H Gillespie
If improvements are to be made in tuberculosis (TB) treatment, an increased understanding of disease in the lung is needed. Studies have shown that bacteria in a less metabolically active state, associated with the presence of lipid bodies, are less susceptible to antibiotics, and recent results have highlighted the disparity in concentration of different compounds into lesions. Treatment success therefore depends critically on the responses of the individual bacteria that constitute the infection. We propose a hybrid, individual-based approach that analyses spatio-temporal dynamics at the cellular level, linking the behaviour of individual bacteria and host cells with the macroscopic behaviour of the microenvironment...
March 7, 2018: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/29523332/an-iclr-like-protein-from-mycobacteria-regulates-leucd-operon-and-induces-dormancy-like-growth-arrest-in-mycobacterium-smegmatis
#8
Rajendra Kumar Angara, Suhail Yousuf, Shailesh Kumar Gupta, Akash Ranjan
leuCD operon encodes isopropylmalate isomerase (IPMI), an essential enzyme in leucine biosynthesis. Leucine biosynthesis is one of the essential metabolic pathways for Mycobacterium tuberculosis survival inside the macrophage. In this study, we identified an IclR like transcription regulator, Rv2989 involved in regulation of leuCD expression. Further, we have shown that the Rv2989 binding site overlaps with the promoter region of leuCD, indicating its direct involvement in the regulation of this operon. Ectopic expression of Rv2989 in M...
January 2018: Tuberculosis
https://www.readbyqxmd.com/read/29485123/triacylglycerol-nourishing-molecule-in-endurance-of-mycobacterium-tuberculosis
#9
Pratap C Mali, Laxman S Meena
The ability of Mycobacterium tuberculosis (M. tuberculosis) to accumulate lipid-rich molecules as an energy source obtained from host cell debris remains interesting. Additionally, the potential of M. tuberculosis to survive under different stress conditions leading to its dormant state in pathogenesis remains elusive. The exact mechanism by which these lipid bodies generated in M. tuberculosis infection and utilized by bacilli inside infected macrophage for its survival is still not understood. In this, during bacillary infection, many metabolic pathways are involved that influence the survival of M...
March 2018: Journal of Biosciences
https://www.readbyqxmd.com/read/29475946/the-anaplerotic-node-is-essential-for-the-intracellular-survival-of-mycobacterium-tuberculosis
#10
Piyali Basu, Noor Sanhu, Apoorva Bhatt, Albel Singh, Ricardo Balhana, Irene Gobe, Nicola A Crowhurst, Tom A Mendum, Liang Gao, Jane L Ward, Mike Beale, Johnjoe McFadden, Dany Jv Beste
Enzymes at the PEP-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis and anaplerosis. Here we use genetic, biochemical and13 C isotopomer analysis to characterize the role of the enzymes at the ANA node during the intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis ( Mtb ). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb   We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29472294/impact-of-the-epoxide-hydrolase-ephd-on-the-metabolism-of-mycolic-acids-in-mycobacteria
#11
Jan Madacki, Françoise Laval, Anna Grzegorzewicz, Anne Lemassu, Monika Záhorszká, Michael Arand, Michael McNeil, Mamadou Daffé, Mary Jackson, Marie-Antoinette Lanéelle, Jana Korduláková
Mycolic acids are the hallmark of the cell envelope in mycobacteria, which include the important human pathogens Mycobacterium tuberculosis and M. leprae Mycolic acids are very long C60-C90 α-alkyl β-hydroxy fatty acids having a variety of functional groups on their hydrocarbon chain that define several mycolate types. Mycobacteria also produce an unusually large number of putative epoxide hydrolases, but the physiological functions of these enzymes are still unclear. Here, we report that the mycobacterial epoxide hydrolase EphD is involved in mycolic acid metabolism...
February 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29467300/high-throughput-metabolomic-analysis-predicts-mode-of-action-of-uncharacterized-antimicrobial-compounds
#12
Mattia Zampieri, Balazs Szappanos, Maria Virginia Buchieri, Andrej Trauner, Ilaria Piazza, Paola Picotti, Sébastien Gagneux, Sonia Borrell, Brigitte Gicquel, Joel Lelievre, Balazs Papp, Uwe Sauer
Rapidly spreading antibiotic resistance and the low discovery rate of new antimicrobial compounds demand more effective strategies for early drug discovery. One bottleneck in the drug discovery pipeline is the identification of the modes of action (MoAs) of new compounds. We have developed a rapid systematic metabolome profiling strategy to classify the MoAs of bioactive compounds. The method predicted MoA-specific metabolic responses in the nonpathogenic bacterium Mycobacterium smegmatis after treatment with 62 reference compounds with known MoAs and different metabolic and nonmetabolic targets...
February 21, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29388150/rv0646c-an-esterase-from-m-tuberculosis-up-regulates-the-host-immune-response-in-thp-1-macrophages-cells
#13
Ruchi Rastogi, Arbind Kumar, Jagdeep Kaur, Varinder Saini, Jasbinder Kaur, Archana Bhatnagar
The genome sequence of Mycobacterium tuberculosis revealed the presence of several hydrolases involved in lipid metabolism including the members of Lip gene family. Rv0646c (LipG) is one of them. It is annotated as putative esterase/lipase because of the presence of consensus sequence 'GXSXG.' The gene was cloned, expressed, and purified in E. coli. It showed 22 U/mg specific activity with pNP-butyrate as a preferred substrate. However, it actively worked on substrates with short chain. The enzyme was optimally active at 50 °C/pH 8...
January 31, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29345343/mycobacterium-tuberculosis-rewiring-host-cell-signaling-to-promote-infection
#14
REVIEW
Michael D Stutz, Michelle P Clark, Marcel Doerflinger, Marc Pellegrini
The ability of Mycobacterium tuberculosis to cause disease hinges upon successfully thwarting the innate defenses of the macrophage host cell. The pathogen's trump card is its armory of virulence factors that throw normal host cell signaling into disarray. This process of subverting the macrophage begins upon entry into the cell, when M. tuberculosis actively inhibits the fusion of the bacilli-laden phagosomes with lysosomes. The pathogen then modulates an array of host signal transduction pathways, which dampens the macrophage's host-protective cytokine response, while simultaneously adapting host cell metabolism to stimulate lipid body accumulation...
December 15, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29301937/cyclipostins-and-cyclophostin-analogs-inhibit-the-antigen-85c-from-mycobacterium-tuberculosis-both-in-vitro-and-in-vivo
#15
Albertus Viljoen, Matthias Richard, Phuong Chi Nguyen, Patrick Fourquet, Luc Camoin, Rishi R Paudal, Giri R Gnawali, Christopher D Spilling, Jean-François Cavalier, Stéphane Canaan, Mickael Blaise, Laurent Kremer
An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of cyclipostins and cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds...
February 23, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29247215/the-transcriptome-of-mycobacterium-tuberculosis-in-a-lipid-rich-dormancy-model-through-rnaseq-analysis
#16
Diana A Aguilar-Ayala, Laurentijn Tilleman, Filip Van Nieuwerburgh, Dieter Deforce, Juan Carlos Palomino, Peter Vandamme, Jorge A Gonzalez-Y-Merchand, Anandi Martin
Tuberculosis (TB) is currently the number one killer among infectious diseases worldwide. Lipids are abundant molecules during the infectious cycle of Mycobacterium tuberculosis (Mtb) and studies better mimicking its actual metabolic state during pathogenesis are needed. Though most studies have focused on the mycobacterial lipid metabolism under standard culture conditions, little is known about the transcriptome of Mtb in a lipid environment. Here we determined the transcriptome of Mtb H37Rv in a lipid-rich environment (cholesterol and fatty acid) under aerobic and hypoxic conditions, using RNAseq...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29245963/identification-of-potential-metabolic-biomarkers-of-cerebrospinal-fluids-that-differentiate-tuberculous-meningitis-from-other-types-of-meningitis-by-a-metabolomics-study
#17
Yi-Ning Dai, Hai-Jun Huang, Wen-Yuan Song, Yong-Xi Tong, Dan-Hong Yang, Ming-Shan Wang, Yi-Cheng Huang, Mei-Juan Chen, Jia-Jie Zhang, Ze-Ze Ren, Wei Zheng, Hong-Ying Pan
Tuberculous meningitis (TBM) is caused by tuberculosis infection of of the meninges, which are the membrane systems that encircle the brain, with a high morbidity and mortality rate. It is challenging to diagnose TBM among other types of meningitis, such as viral meningitis, bacterial meningitis and cryptococcal meningitis. We aimed to identify metabolites that are differentially expressed between TBM and the other types of meningitis by a global metabolomics analysis. The cerebrospinal fluids (CSF) from 50 patients with TBM, 17 with viral meningitis, 17 with bacterial meningitis, and 16 with cryptococcal meningitis were analyzed using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS)...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29208413/characterization-of-ml0314c-of-mycobacterium-leprae-and-deciphering-its-role-in-the-immune-response-in-leprosy-patients
#18
Gurkamajit Kaur, Aashish Sharma, Tarun Narang, Sunil Dogra, Jagdeep Kaur
Mycobacterium leprae has a reduced genome size due to the reductive evolution over a long period of time. Lipid metabolism plays an important role in the life cycle and pathogenesis of this bacterium. In comparison to 26 lip genes (Lip A-Z) of M. tuberculosis, M. leprae retained only three orthologs indicating their importance in its life cycle. ML0314c (LipU) is one of them. It is conserved throughout the mycobacterium species. Bioinformatics analysis showed the presence of an α/β hydrolase fold and 'GXSXG' characteristic of the esterases/lipases...
February 15, 2018: Gene
https://www.readbyqxmd.com/read/29190491/lipid-metabolism-and-its-implication-in-mycobacteria-host-interaction
#19
REVIEW
Gabriela Gago, Lautaro Diacovich, Hugo Gramajo
The complex lipids present in the cell wall of Mycobacterium tuberculosis (Mtb) act as major effector molecules that actively interact with the host, modulating its metabolism and stimulating the immune response, which in turn affects the physiology of both, the host cell and the bacilli. Lipids from the host are also nutrient sources for the pathogen and define the fate of the infection by modulating lipid homeostasis. Although new technologies and experimental models of infection have greatly helped understanding the different aspects of the host-pathogen interactions at the lipid level, the impact of this interaction in the Mtb lipid regulation is still incipient, mainly because of the low background knowledge in this area of research...
November 27, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29143876/deregulation-of-genes-associated-with-alternate-drug-resistance-mechanisms-in-mycobacterium-tuberculosis
#20
Kalpana Sriraman, Kayzad Nilgiriwala, Dhananjaya Saranath, Anirvan Chatterjee, Nerges Mistry
Alternate mechanisms of drug resistance involving intrinsic defense pathways play an important role in development of drug resistance. Deregulation of drug efflux, cellular metabolism, and DNA repair have been indicated to have effect on drug tolerance and persistence. Here we chose eight genes from these pathways to investigate their association with development of multidrug resistance (MDR). We generated mono drug resistant and MDR strains of rifampicin and isoniazid and examined the differential expression of genes belonging to efflux, DNA repair and cell wall lipid synthesis pathways...
November 16, 2017: Current Microbiology
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