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Lipid metabolism tuberculosis

Fernando Vargas-Romero, Guillermo Mendoza-Hernández, Francisco Suarez-Güemes, Rogelio Hernández-Pando, Mauricio Castañón-Arreola
Mycobacterium bovis is the causative agent of tuberculosis in farms, wildlife and causes sporadic disease in humans. Despite the high similitude in genome sequence between M. bovis strains, some strains like the wild boar 04-303 isolate show a highly virulent phenotype in animal models. Comparative studies will contribute to link protein expression with the virulence phenotype. In vitro, the 04-303 strain was more phagocytized by J774A.1 macrophages in comparison with 444 strain (a cow isolate with the same genotype) and BCG...
October 18, 2016: Microbial Pathogenesis
Yaroslav Faletrov, Anna Brzostek, Renata Plocinska, Jarosław Dziadek, Elena Rudaya, Irina Edimecheva, Vladimir Shkumatov
Fluorescent steroids BODIPY-cholesterol (BPCh) and 7-nitrobenzoxadiazole-4-amino-(NBD)-labeled 22-NBD-chelesterol (22NC) as well as synthesized 20-(NBD)-pregn-5-en-3β-ol (20NP) were found to undergo bioconversions by Mycobacterium tuberculosis H37Rv and M. smegmatis mc(2) 155. The major fluorescent products were determined to be 4-en-3-one derivatives of the compounds. Degradation of NBD fluorophore was also detected in the cases of 22NC and 20NP, but neither NBD degradation nor steroidal part modification were observed for the synthesized 3-(NBD)-cholestane...
October 5, 2016: Steroids
Peicheng Du, Charles D Sohaskey, Lanbo Shi
Mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. While active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of M. tuberculosis reactivation are still poorly understood. We characterized the physiology and global transcriptomic profiles of M. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. We found that M. tuberculosis reactivation upon reaeration was associated with a lag phase, in which the recovery of cellular physiological and metabolic functions preceded the resumption of cell replication...
2016: Frontiers in Microbiology
Neha Agrawal, Chandrika Bhattacharyya, Ankur Mukherjee, Ubaid Ullah, Bhaswati Pandit, Kanury V S Rao, Partha P Majumder
Incomplete understanding of mechanisms involved in the host-pathogen interactions constrains our efforts to eliminate tuberculosis. In many individuals, resulting from immune response to mycobacterial infection organised structures called granulomas are formed. To identify host responses that may control at least the early stages of infection, we employed an in vitro granuloma model. Here, human PBMCs were infected with live Mycobacterium tuberculosis in culture, and the appearance of granuloma-like structures was monitored over the next several days...
September 2016: Tuberculosis
Paula Az Campanerut-Sá, Luciana D Ghiraldi-Lopes, Jean E Meneguello, Adriana Fiorini, Geisa Pc Evaristo, Vera Ld Siqueira, Regiane Bl Scodro, Eliana V Patussi, Lucélia Donatti, Emanuel M Souza, Rosilene F Cardoso
AIM: To study the proteomic and morphological changes in Mycobacterium tuberculosis H37Rv exposed to subinhibitory concentration of isoniazid (INH). MATERIALS & METHODS: The bacillus was exposed to ½ MIC of INH at 12, 24 and 48 h. The samples' cells were submitted to scanning electron microscopy. The proteins were separated by 2D gel electrophoresis and identified by MS. RESULTS: INH exposure was able to alter the format, the multiplication and causing a cell swelling in the bacillus...
September 2016: Future Microbiology
Glynis Johnson
The α/β hydrolase fold superfamily is an ancient and widely diversified group of primarily hydrolytic enzymes. In this review, the adaptations of these proteins to the pathogenic lifestyle of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, are examined. Of the 105 α/β hydrolases identified in Mtb, many are associated with lipid metabolism, particularly in the biosynthesis and maintenance of the Mtb's unique cell envelope, as well in the large number of extracellular lipases that are likely responsible for degradation of host lipid material...
July 28, 2016: Current Protein & Peptide Science
Maikel Boot, Marion Sparrius, Kin Ki Jim, Susanna Commandeur, Alexander Speer, Robert van de Weerd, Wilbert Bitter
Tuberculosis can be treated with a 6-month regimen of antibiotics. Although the targets of most of the first-line antibiotics have been identified, less research has focused on the intrabacterial stress responses that follow upon treatment with antibiotics. Studying the roles of these stress genes may lead to the identification of crucial stress-coping mechanisms that can provide additional drug targets to increase treatment efficacy. A three-gene operon with unknown function that is strongly up-regulated upon treatment with isoniazid and ethambutol is the iniBAC operon...
September 16, 2016: Journal of Biological Chemistry
N Dong, Y R Fu, Z J Yi
No abstract text is available yet for this article.
July 2016: Chinese Journal of Tuberculosis and Respiratory Diseases
Qiming Li, Mingliang Zhou, Xiangyu Fan, Jianlong Yan, Weimin Li, Jianping Xie
M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS...
2016: Scientific Reports
Jaiyanth Daniel, Nidhi Kapoor, Tatiana Sirakova, Rajesh Sinha, Pappachan Kolattukudy
Mycobacterium tuberculosis (Mtb) causes latent tuberculosis infection in one-third of the world population and remains quiescent in the human body for decades. The dormant pathogen accumulates lipid droplets containing triacylglycerol (TAG). In mammals, perilipin regulates lipid droplet homeostasis but no such protein has been identified in Mtb. We identified an Mtb protein (PPE15) that showed weak amino acid sequence identities with mammalian perilipin-1 and was upregulated in Mtb dormancy. We generated a ppe15 gene-disrupted mutant of Mtb and examined its ability to metabolically incorporate radiolabeled oleic acid into TAG, accumulate lipid droplets containing TAG and develop phenotypic tolerance to rifampicin in two in vitro models of dormancy including a three-dimensional human granuloma model...
September 2016: Molecular Microbiology
Annaïk Quémard
Mycolic acids are extremely-long-chain fatty acids that compose a large family of mycolate-containing compounds, major envelope lipid components and critical pathogenicity factors of Mycobacterium tuberculosis. In recent years there have been major advances in understanding their metabolic pathway. Unknown enzymes of the fatty acid synthase type II elongation system and the condensation system that builds the mycolic acid scaffold were identified. Missing links with the mycolate-containing compound biosynthesis-such as the mechanisms of transfer onto trehalose and of translocation through the inner membrane-were deciphered, while recycling processes have emerged...
September 2016: Trends in Microbiology
Aaron Olsen, Yong Chen, Qingzhou Ji, Guofeng Zhu, Aruna Dharshan De Silva, Catherine Vilchèze, Torin Weisbrod, Weimin Li, Jiayong Xu, Michelle Larsen, Jinghang Zhang, Steven A Porcelli, William R Jacobs, John Chan
UNLABELLED: Tumor necrosis factor alpha (TNF) plays a critical role in the control of Mycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4(+) T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8(+) T cells). M. tuberculosis can evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components...
2016: MBio
Jingfeng Tong, Lu Meng, Xinwei Wang, Lixia Liu, Liangdong Lyu, Chuan Wang, Yang Li, Qian Gao, Chen Yang, Chen Niu
Lipids have been identified as important carbon sources for Mycobacterium tuberculosis (Mtb) to utilize in vivo. Thus gluconeogenesis bears a key role for Mtb to survive and replicate in host. A rate-limiting enzyme of gluconeogenesis, fructose 1, 6-bisphosphatase (FBPase) is encoded by the gene glpX. The functions of glpX were studied in M. marinum, a closely related species to Mtb. The glpX deletion strain (ΔglpX) displayed altered gluconeogenesis, attenuated virulence, and altered bacterial proliferation...
2016: PloS One
Gérald Larrouy-Maumus, Leonardo B Marino, Ashoka V R Madduri, T J Ragan, Debbie M Hunt, Lucrezia Bassano, Maximiliano G Gutierrez, D Branch Moody, Fernando R Pavan, Luiz Pedro S de Carvalho
The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d-cycloserine, several aminoglycosides, and quinolones...
May 13, 2016: ACS Infectious Diseases
Wanisa Salaemae, Grant W Booker, Steven W Polyak
Biotin is an essential cofactor for enzymes present in key metabolic pathways such as fatty acid biosynthesis, replenishment of the tricarboxylic acid cycle, and amino acid metabolism. Biotin is synthesized de novo in microorganisms, plants, and fungi, but this metabolic activity is absent in mammals, making biotin biosynthesis an attractive target for antibiotic discovery. In particular, biotin biosynthesis plays important metabolic roles as the sole source of biotin in all stages of the Mycobacterium tuberculosis life cycle due to the lack of a transporter for scavenging exogenous biotin...
April 2016: Microbiology Spectrum
Heather L Torrey, Iris Keren, Laura E Via, Jong Seok Lee, Kim Lewis
Mycobacterium tuberculosis forms drug-tolerant persister cells that are the probable cause of its recalcitrance to antibiotic therapy. While genetically identical to the rest of the population, persisters are dormant, which protects them from killing by bactericidal antibiotics. The mechanism of persister formation in M. tuberculosis is not well understood. In this study, we selected for high persister (hip) mutants and characterized them by whole genome sequencing and transcriptome analysis. In parallel, we identified and characterized clinical isolates that naturally produce high levels of persisters...
2016: PloS One
Saikou Y Bah, Paul Dickinson, Thorsten Forster, Beate Kampmann, Peter Ghazal
Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signaling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signaling to regulate the dynamics of cholesterol synthesis and homeostasis...
May 4, 2016: Journal of Steroid Biochemistry and Molecular Biology
Jennifer M Hayashi, Chu-Yuan Luo, Jacob A Mayfield, Tsungda Hsu, Takeshi Fukuda, Andrew L Walfield, Samantha R Giffen, John D Leszyk, Christina E Baer, Owen T Bennion, Ashoka Madduri, Scott A Shaffer, Bree B Aldridge, Christopher M Sassetti, Steven J Sandler, Taroh Kinoshita, D Branch Moody, Yasu S Morita
Protected from host immune attack and antibiotic penetration by their unique cell envelope, mycobacterial pathogens cause devastating human diseases such as tuberculosis. Seamless coordination of cell growth with cell envelope elongation at the pole maintains this barrier. Unraveling this spatiotemporal regulation is a potential strategy for controlling mycobacterial infections. Our biochemical analysis previously revealed two functionally distinct membrane fractions in Mycobacterium smegmatis cell lysates: plasma membrane tightly associated with the cell wall (PM-CW) and a distinct fraction of pure membrane free of cell wall components (PMf)...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Abhishek Trivedi, Parminder Singh Mavi, Deepak Bhatt, Ashwani Kumar
Mycobacterium tuberculosis (Mtb) forms biofilms harbouring antibiotic-tolerant bacilli in vitro, but the factors that induce biofilm formation and the nature of the extracellular material that holds the cells together are poorly understood. Here we show that intracellular thiol reductive stress (TRS) induces formation of Mtb biofilms in vitro, which harbour drug-tolerant but metabolically active bacteria with unchanged levels of ATP/ADP, NAD(+)/NADH and NADP(+)/NADPH. The development of these biofilms requires DNA, RNA and protein synthesis...
2016: Nature Communications
Mireille Ouimet, Stefan Koster, Erik Sakowski, Bhama Ramkhelawon, Coen van Solingen, Scott Oldebeken, Denuja Karunakaran, Cynthia Portal-Celhay, Frederick J Sheedy, Tathagat Dutta Ray, Katharine Cecchini, Philip D Zamore, Katey J Rayner, Yves L Marcel, Jennifer A Philips, Kathryn J Moore
Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy...
June 2016: Nature Immunology
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