Publications

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real-time sequencing of mycobacterium tuberculosis: are we there yet?whole genome sequencing has taken a leading role in epidemiologic studies of tuberculosis, but thus far, the real-time, clinical utility has been low, in part due to the requirement for culture. in votintseva et al (j clin microbiol https://doi.org/10.1128/jcm.02483-16), authors present a new method for extracting mycobacterium tuberculosis dna directly from smear-positive respiratory samples, generating drug resistance predictions and phylogenetic trees in 44 hours using the illumina miseq. aut ...201728298449
structure of the complex between a heparan sulfate octasaccharide and mycobacterial heparin-binding hemagglutinin.heparin-binding hemagglutinin (hbha) is a 199 amino acid virulence factor at the envelope of mycobacterium tuberculosis that contributes to latent tuberculosis. the binding of hbha to respiratory epithelial cells, which leads to extrapulmonary dissemination of the pathogen, is mediated by cell-surface heparan sulfate (hs). we report the structural characterization of the hbha/hs complex by nmr spectroscopy. to develop a model for the molecular recognition, the first chemically synthesized unifor ...201728294485
promoting adherence to treatment for latent tb infection through mobile phone text messaging: study protocol for a pilot randomized controlled trial.an estimated two billion people, over one third of the world's population, have latent infection with mycobacterium tuberculosis (ltbi). patient adherence to ltbi treatment is currently poor given that individuals show no symptoms of illness and may not feel that they are at risk of developing active tuberculosis (tb). short text messages can serve as a simple reminder to take medications and address barriers to adherence such as forgetfulness and lack of social support.201728293431
cfp10: mfcγ2 as a novel tuberculosis vaccine candidate increases immune response in mouse.despite treatment with antibiotics and vaccination with bcg, tuberculosis (tb) is still considered as one of the most important public health problems in the world. therefore, designing and producing a more effective vaccine against tb seems urgently. in this study, immunogenicity of a fusion protein which consisting or comprising cfp-10 from mycobacterium tuberculosis and the fc-domain of mouse igg2a was evaluated as a novel subunit vaccine candidate against tb.201728293387
interferon lambda: modulating immunity in infectious diseases.interferon lambdas (ifn-λs; ifnl1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. ifn-λs act by binding to the heterodimeric ifn-λ receptor (ifnlr), activating a stat phosphorylation-dependent signaling cascade. thereby hundreds of ifn-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. when compared to the well-characterized ifn-α signaling cascade, three important difference ...201728293236
nanostructured lipid carriers for incorporation of copper(ii) complexes to be used against mycobacterium tuberculosis.tuberculosis (tb) is a disease caused by mycobacterium tuberculosis. cessation of treatment before the recommended conclusion may lead to the emergence of multidrug-resistant strains. the aim of this study was to develop nanostructured lipid carriers (nlcs) for use in the treatment of m. tuberculosis. the nlcs comprised the following lipid phase: 2.07% polyoxyethylene 40 stearate, 2.05% caprylic/capric triglyceride, and 0.88% polyoxyl 40 hydrogenated castor oil; the following aqueous phase: 3.50 ...201728356717
pharmacokinetic-pharmacodynamic modelling of intracellular mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.tuberculosis (tb) treatment is long and complex, typically involving a combination of drugs taken for 6 months. improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to tb drug development is the lack of predictive pre-clinical tools. to address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-tb drugs against intracellular mycobacterium tuberculosis (mtb) res ...201728356552
design, synthesis and experimental validation of peptide ligands targeting mycobacterium tuberculosis σ factors.transcription in prokaryotes is a multi-step process and is primarily regulated at the initiation stage. sigma factors are involved in promoter recognition and thus govern prokaryotic gene expression. mycobacterium tuberculosis sigma factors have been previously suggested as important drug targets through large-scale genome analyses. here we demonstrate the feasibility of specific targeting of mtb sigma factors using designed peptides. a peptide library was generated using 3-d structural feature ...201728355052
transplanted lungs and the "white plague": a case-report and review of the literature.solid organ transplant recipients, especially after lung transplantation, are at increased risk for mycobacterium tuberculosis pulmonary tuberculosis due to lifelong immunosuppression.201728353558
kanamycin sulphate loaded plga-vitamin-e-tpgs long circulating nanoparticles using combined coating of peg and water-soluble chitosan.kanamycin sulphate (ks) is a mycobacterium tuberculosis protein synthesis inhibitor. due to its intense hydrophilicity, ks is cleared from the body within 8 h. ks has a very short plasma half-life (2.5 h). ks is used in high concentrations to reach the therapeutic levels in plasma, which results in serious nephrotoxicity/ototoxicity. to overcome aforementioned limitations, the current study aimed to develop ks loaded plga-vitamin-e-tpgs nanoparticles (ks-plga-tpgs nps), to act as an efficient ca ...201728352475
structure of the mazf-mt9 toxin, a trna-specific endonuclease from mycobacterium tuberculosis.tuberculosis (tb) is a severe disease caused by mycobacterium tuberculosis (m. tb) and the well-characterized m. tb maze/f proteins play important roles in stress adaptation. recently, the mazf-mt9 toxin has been found to display endonuclease activities towards trnas but the mechanism is unknown. we hereby present the crystal structure of apo-mazf-mt9. the enzyme recognizes trna(lys) with a central uuu motif within the anticodon loop, but is insensitive to the sequence context outside of the loo ...201728351618
use of whole-genome sequencing to distinguish relapse from reinfection in a completed tuberculosis clinical trial.rifaquin was a tuberculosis chemotherapy trial in southern africa including regimens with high-dose rifapentine with moxifloxacin. here, the application of whole-genome sequencing (wgs) is evaluated within rifaquin for identifying new infections in treated patients as either relapses or reinfections. wgs is further compared with mycobacterial interspersed repetitive units-variable number tandem repeats (miru-vntr) typing. this is the first report of wgs being used to evaluate new infections in a ...201728351427
evaluation of genexpert mtb/rif for detecting mycobacterium tuberculosis in a hospital in china.objective to evaluate the performance of genexpert mtb/rif in diagnosing pulmonary tuberculosis (tb) in china. methods this cross-sectional study included sputum specimens of 240 suspected tb cases. specimens were examined by light microscopy for the presence of acid-fast bacilli, which were cultured by the bactec mgit 960 (m960) system and detected by the genexpert mtb/rif assay. the positive rate, sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv), and a ...201728351283
novel sulfamethoxazole ureas and oxalamide as potential antimycobacterial agents.infections caused by mycobacterium tuberculosis (mtb.) and nontuberculous mycobacteria (ntm) are considered to be a global health problem; current therapeutic options are limited. sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. based on the activity of 4-(3-heptylureido)-n-(5-methylisoxazol-3-yl)benzenesulfonamide against ntm, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (c₁-c12), as well as several related ureas ...201728350331
the metabolomic strategy in tuberculosis therapy.tuberculosis causes around 1.4 million deaths every year remaining to be a major cause of morbidity and mortality. mycobacterium tuberculosis is adept at surviving the assault of our immune system, which has perplexed many researchers. not only are they difficult to treat, but also difficult to detect accurately. the current reservoir of drugs and method to diagnose them is depleting faster than we are able to replace them with newer one. the advances made in the field of metabolomic have opened ...201728290241
mycobacterium tuberculosis cpn60.2 (groel2) blocks macrophage apoptosis via interaction with mitochondrial mortalin.earlier studies suggested that mycobacterium tuberculosis (mtb) proteins exported within the host macrophage play an essential role in tuberculosis pathogenesis. in fact, mtb proteins interact with and deactivate key regulators of many macrophage functions such as phago-lysosome fusion and antigen presentation, resulting in the intracellular persistence of pathogenic mycobacteria. cpn60.2 is an abundant mtb chaperone protein, restricted to cell cytoplasm and surface, that was reported to be esse ...201728288970
immunological diagnosis as an adjunctive tool for an early diagnosis of tuberculous meningitis of an immune competent child in a low tuberculosis endemic country: a case report.pediatric tuberculous meningitis is a highly morbid, often fatal disease. its prompt diagnosis and treatment saves lives, in fact delays in the initiation of therapy have been associated with high mortality rates.201728288691
rapid one-step enzymatic synthesis and all-aqueous purification of trehalose analogues.chemically modified versions of trehalose, or trehalose analogues, have applications in biology, biotechnology, and pharmaceutical science, among other fields. for instance, trehalose analogues bearing detectable tags have been used to detect mycobacterium tuberculosis and may have applications as tuberculosis diagnostic imaging agents. hydrolytically stable versions of trehalose are also being pursued due to their potential for use as non-caloric sweeteners and bioprotective agents. despite the ...201728287534
novel pharmacological activity of artesunate and artemisinin: their potential as anti-tubercular agents.tuberculosis is a major infectious disease that globally causes the highest human mortality. from this aspect, this study was carried out to evaluate novel pharmacological activities/effects of artesunate and artemisinin causing anti-tubercular activity/effects against mycobacterium tuberculosis (mtb). the anti-mtb activities/effects of artesunate and artemisinin were evaluated using different anti-mtb indicator assays, such as the resazurin microtiter assay, the mycobacteria growth indicator tu ...201728287416
structural insights into the ethr-dna interaction using native mass spectrometry.ethr is a transcriptional repressor that increases mycobacterium tuberculosis resistance to ethionamide. in this study, the ethr-dna interaction has been investigated by native electrospray-ionization mass spectrometry for the first time. the results show that up to six subunits of ethr are able to bind to its operator.201728287239
synthesis and antibacterial activity of 3-benzylamide derivatives as ftsz inhibitors.the emergence and spread of multidrug-resistant strains of the human pathological bacteria are generating a threat to public health worldwide. in the current study, a series of pc190723 derivatives was synthesized and investigated for their antimicrobial activity. the compounds exhibited good activity against several gram-positive bacteria as determined by comparison of diameters of the zone of inhibition of test compounds and standard antibiotics. compound 9 with a fluorine substitution on the ...201728285910
exploring covalent allosteric inhibition of antigen 85c from mycobacterium tuberculosis by ebselen derivatives.previous studies identified ebselen as a potent in vitro and in vivo inhibitor of the mycobacterium tuberculosis (mtb) antigen 85 (ag85) complex, comprising three homologous enzymes required for the biosynthesis of the mycobacterial cell wall. in this study, the mtb ag85c enzyme was cocrystallized with azido and adamantyl ebselen derivatives, resulting in two crystallographic structures of 2.01 and 1.30 å resolution, respectively. both structures displayed the anticipated covalent modification o ...201728285521
bioengineered 3d models for studying human cell-tuberculosis interactions.in vivo animal models have intrinsic limitations for studying relationships between tuberculosis and its host and there is a need for alternative, in vitro cellular models. a microsphere-based 3d in vitro culture system of mycobacterium tuberculosis-infected human blood mononuclear cells was reported to address specific aspects of host-pathogen interactions.201728284875
multiplex detection of extensively drug resistant tuberculosis using binary deoxyribozyme sensors.current diagnostic tools for mycobacterium tuberculosis (mtb) have many disadvantages including low sensitivity, slow turnaround times, or high cost. accurate, easy to use, and inexpensive point of care molecular diagnostic tests are urgently needed for the analysis of multidrug resistant (mdr) and extensively drug resistant (xdr) mtb strains that emerge globally as a public health threat. in this study, we established proof-of-concept for a novel diagnostic platform (tb-dzt) for mtb detection a ...201728284077
transcriptome analysis of mycobacteria in sputum samples of pulmonary tuberculosis patients.pulmonary tuberculosis, the disease caused by mycobacterium tuberculosis, still retains a top rank among the deadliest communicable diseases. sputum expectorated during the disease continues to be a primary diagnostic specimen and also serves as a reservoir of bacteria. the expression pattern of mycobacteria in sputum will lead to an insight into bacterial adaptation at the most highly transmissible stage of infection and can also help in identifying newer diagnostic as well as drug targets. thu ...201728282458
synthesis of transition-state inhibitors of chorismate utilizing enzymes from bromobenzene cis-1,2-dihydrodiol.in order to survive in a mammalian host, mycobacterium tuberculosis (mtb) produces aryl-capped siderophores known as the mycobactins for iron acquisition. salicylic acid is a key building block of the mycobactin core and is synthesized by the bifunctional enzyme mbti, which converts chorismate into isochorismate via a sn2″ reaction followed by further transformation into salicylate through a [3,3]-sigmatropic rearrangement. mbti belongs to a family of chorismate-utilizing enzymes (cues) that hav ...201728282140
naphthofuroquinone derivatives show strong antimycobacterial activities against drug-resistant mycobacteria.tuberculosis, one of the world's major health problems, has become more serious due to the emergence of multi-drug resistant (mdr) and extensively drug-resistant (xdr) mycobacterium tuberculosis (mtb). in this study, we performed three anti-mtb assays to evaluate the anti-mycobacterial activity of naphthofuroquinone derivatives against drug-resistant mtb. among them, methyl 5-[2-(dimethylamino)ethoxy]-7,12-dioxo-7,12-dihydrodinaphtho[1,2-b:2',3'-d]furan-6-carboxylate (dfc2) exhibited strong anti ...201728281912
miliary tuberculosis.miliary tuberculosis (tb) results from a massive lymphohematogenous dissemination of mycobacterium tuberculosis bacilli and is characterized by tiny tubercles evident on gross pathology resembling millet seeds in size and appearance. the global hiv/aids pandemic and widespread use of immunosuppressive drugs and biologicals have altered the epidemiology of miliary tb. considered to be predominantly a disease of infants and children in the pre-antibiotic era, miliary tb is increasingly being encou ...201728281441
epigenetic phosphorylation control of mycobacterium tuberculosis infection and persistence.reversible protein phosphorylation is the most common type of epigenetic posttranslational modification in living cells used as a major regulation mechanism of biological processes. the mycobacterium tuberculosis genome encodes for 11 serine/threonine protein kinases that are responsible for sensing environmental signals to coordinate a cellular response to ensure the pathogen's infectivity, survival, and growth. to overcome killing mechanisms generated within the host during infection, m. tuber ...201728281439
myeloid and t cell-derived tnf protects against central nervous system tuberculosis.tuberculosis of the central nervous system (cns-tb) is a devastating complication of tuberculosis, and tumor necrosis factor (tnf) is crucial for innate immunity and controlling the infection. tnf is produced by many cell types upon activation, in particularly the myeloid and t cells during neuroinflammation. here we used mice with tnf ablation targeted to myeloid and t cell (mt-tnf(-/-)) to assess the contribution of myeloid and t cell-derived tnf in immune responses during cns-tb. these mice e ...201728280495
in silico discovery and in vitro activity of inhibitors against mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (mtb bioa).computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. the enzyme 7,8-diaminopelargonic acid aminotransferase (bioa) in mycobacterium tuberculosis (mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. the c ...201728280303
structure-activity relationship studies on 3,5-dinitrophenyl tetrazoles as antitubercular agents.in this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. these simple and readily accessible compounds possessed high in vitro antimycobacterial activities against mycobacterium tuberculosis, including clinically isolated multidrug (mdr) and extensively drug-resistant (xdr) strains, with submicromolar minimum inhibitory concentrations (mics). the most promising compounds showed low in vitro cytotoxicity and negl ...201728279848
tuberculosis.essential facts tuberculosis (tb) is an infection caused by a bacterium, mycobacterium tuberculosis. while it can affect any part of the body, only pulmonary tb is infectious. according to the charity tb alert, there were 5,758 cases of tb in the uk in 2015 and 39% of them were in london. this represented a fall from a peak of 8,919 cases in 2011. left untreated, tb is life-threatening, but is usually curable with antibiotics. the sooner it is diagnosed and treated, the better, both for the pers ...201728279091
enhanced control of mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine.currently there are a dozen or so of new vaccine candidates in clinical trials for prevention of tuberculosis (tb) and each formulation attempts to elicit protection by enhancement of cell-mediated immunity (cmi). in contrast, most approved vaccines against other bacterial pathogens are believed to mediate protection by eliciting antibody responses. however, it has been difficult to apply this formula to tb because of the difficulty in reliably eliciting protective antibodies. here, we developed ...201728278283
ppar-α activation mediates innate host defense through induction of tfeb and lipid catabolism.the role of peroxisome proliferator-activated receptor α (ppar-α) in innate host defense is largely unknown. in this study, we show that ppar-α is essential for antimycobacterial responses via activation of transcription factor eb (tfeb) transcription and inhibition of lipid body formation. ppar-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. ppar-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation ...201728275133
rapid detection of cell-free mycobacterium tuberculosis dna in tuberculous pleural effusion.tuberculous pleurisy is one of the most common extra-pulmonary tuberculosis, but its diagnosis remains to be difficult. in this study, we for the first time report detection of cell-free mycobacterium tuberculosis dna in pleural effusion and evaluation of this newly developed molecular assay. a total of 78 patients with pleural effusion, 60 patients with tuberculous pleurisy and 18 patients with alternative diseases, were included in this study. mycobacterial culture, xpert mtb/rif assay, adenos ...201728275073
three-component, one-pot synthesis of anthranilamide schiff bases bearing 4-aminoquinoline moiety as mycobacterium tuberculosis gyrase inhibitors.an efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-n-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. all synthesized compounds were evaluated for their antimycobacterial activity against mycobacterium tuberculosis (mtb) and cytotoxicity activity against ...201728274627
comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis.timely and accurate identification of people with latent tuberculosis infection (ltbi) is important for controlling mycobacterium tuberculosis (tb). there is no gold standard for diagnosis of ltbi. screening tests such as interferon gamma release assays (igras) and tuberculin skin test (tst) provide indirect and imperfect information. this systematic review compared two types of igras quantiferon®-tb gold in-tube test (qft-git) and t-spot.tb with tst for identification of ltbi by predicting prog ...201728274215
thermal and photoinduced copper-promoted c-se bond formation: synthesis of 2-alkyl-1,2-benzisoselenazol-3(2h)-ones and evaluation against mycobacterium tuberculosis.2-alkyl-1,2-benzisoselenazol-3(2h)-ones, represented by ebselen (1a), are being studied intensively for a range of medicinal applications. we describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (ksecn) and n-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2h)-ones containing a c-se-n bond. the copper ligand (1,10-phenanthroline) facilitates c-se bond formation during heating via a mechanism that likely involves atom ...201728273423
mechanism-based inhibition of the mycobacterium tuberculosis branched-chain aminotransferase by d- and l-cycloserine.the branched-chain aminotransferase is a pyridoxal 5'-phosphate (plp)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, l-leucine, l-isoleucine, and l-valine, in bacteria. we have investigated the mechanism of inactivation of the branched-chain aminotransferase from mycobacterium tuberculosis (mtilve) by d- and l-cycloserine. d-cycloserine is currently used only in the treatment of multidrug-drug-resistant tuberculosis. our results show ...201728272868
scrutiny of mycobacterium tuberculosis 19 kda antigen proteoforms provides new insights in the lipoglycoprotein biogenesis paradigm.post-translational modifications (ptms) are essential processes conditioning the biophysical properties and biological activities of the vast majority of mature proteins. however, occurrence of several distinct ptms on a same protein dramatically increases its molecular diversity. the comprehensive understanding of the functionalities resulting from any particular ptm association requires a highly challenging full structural description of the ptm combinations. here, we report the in-depth explo ...201728272507
novel vaccine potential of rv3131, a dosr regulon-encoded putative nitroreductase, against hyper-virulent mycobacterium tuberculosis strain k.accumulating evidence indicates that latency-associated mycobacterium tuberculosis (mtb)-specific antigens from the dormancy survival regulator regulon (dosr) may be promising novel vaccine target antigens for the development of an improved tuberculosis vaccine. after transcriptional profiling of dosr-related genes in the hyper-virulent beijing mtb strain k and the reference mtb strain h37rv, we selected rv3131, a hypothetical nitroreductase, as a vaccine antigen and evaluated its vaccine effica ...201728272457
in vivo-selected pyrazinoic acid-resistant mycobacterium tuberculosis strains harbor missense mutations in the aspartate decarboxylase pand and the unfoldase clpc1.through mutant selection on agar containing pyrazinoic acid (poa), the bioactive form of the prodrug pyrazinamide (pza), we recently showed that missense mutations in the aspartate decarboxylase pand and the unfoldase clpc1, and loss-of-function mutation of polyketide synthases mas and ppsa-e involved in phthiocerol dimycocerosate synthesis, cause resistance to poa and pza in mycobacterium tuberculosis. here we first asked whether these in vitro-selected poa/pza-resistant mutants are attenuated ...201728271875
tuberculosis presenting as bronchoesophageal fistula.we report a case of bronchoesophageal fistula associated with tuberculosis. a 25 year old woman presented to us with 3 month history of cough worsening with deglutition. radiological examination revealed mediastinal lymphadenopathy and bronchoscopy with esophagoscopy confirmed the presence of fistulous communication with features of endobronchial tuberculosis. histological examination of bronchial biopsy specimen showed non necrotic granuloma with the pcr positive for mycobacterium tuberculosis ...201728271046
the cell wall lipid pdim contributes to phagosomal escape and host cell exit of mycobacterium tuberculosis.the cell wall of mycobacterium tuberculosis is composed of unique lipids that are important for pathogenesis. indeed, the first-ever genetic screen in m. tuberculosis identified genes involved in the biosynthesis and transport of the cell wall lipid pdim (phthiocerol dimycocerosates) as crucial for the survival of m. tuberculosis in mice. here we show evidence for a novel molecular mechanism of the pdim-mediated virulence in m. tuberculosis we characterized the dna interaction and the regulon of ...201728270579
design, synthesis and in vitro anti-tuberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4-oxadiazole derivatives.a new anti-tubercular agents, benzo[6,7]cyclohepta[1,2-b]pyridine -1,3,4- oxadiazole hybrids (6a-o) have been designed and synthesized involving oxidative cyclization of hydrazones by use of di(acetoxy)iodobenzene (dib) and characterized by ir,(1) h nmr,(13) c nmr, hrms and further confirmed by x-ray analysis. all the newly synthesized compounds 4a-o evaluated for their in vitro anti-mycobacterial activity against mycobacterium tuberculosis h37rv (atcc27294). among the compounds tested, the comp ...201728267891
glyoxylate detoxification is an essential function of malate synthase required for carbon assimilation in mycobacterium tuberculosis.the glyoxylate shunt is a metabolic pathway of bacteria, fungi, and plants used to assimilate even-chain fatty acids (fas) and has been implicated in persistence of mycobacterium tuberculosis (mtb). recent work, however, showed that the first enzyme of the glyoxylate shunt, isocitrate lyase (icl), may mediate survival of mtb during the acute and chronic phases of infection in mice through physiologic functions apart from fatty acid metabolism. here, we report that malate synthase (ms), the secon ...201728265055
a mathematical model predicting host mitochondrial pyruvate transporter activity to be a critical regulator of mycobacterium tuberculosis pathogenicity.modulation of host metabolic machinery by mycobacterium tuberculosis is a well established phenomenon. in our earlier study (mehrotra et al., 2014), we observed a marked increase in acetyl-coa levels in cells bearing virulent m. tuberculosis infections compared to host cells harbouring avirulent infections. the difference was observed inspite of similar levels of total host cellular pyruvate in both infection types. the present study aimed in capturing the cause for such a phenomenon that define ...201728263840
nitric oxide in cerebrospinal fluid of central nervous system tuberculosis: correlations with culture, antibody response, and cell count.the role of nitric oxide (no) has been established in infection over the years. no functions by inhibiting the growth of intracellular pathogens. the present study was undertaken to ascertain the role of no in central nervous system (cns) infection by mycobacterium tuberculosis.201728263476
exosomes function in antigen presentation during an in vivo mycobacterium tuberculosis infection.mycobacterium tuberculosis-infected macrophages and dendritic cells are limited in their ability to present antigen to cd4+ t cells suggesting that other mechanism of antigen presentation are driving the robust t cell response observed during an m. tuberculosis infection. these mechanisms could include antigens present in apoptotic bodies, necrotic debris, exosomes or even release of non-vesicular antigen from infected cells. however, there is limited data to support any of these mechanisms as i ...201728262829
circulating micrornas as potential biomarkers of infectious disease.micrornas (mirnas) are a class of small non-coding endogenous rna molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. thousands of these molecules have been discovered to date, and multiple mirnas have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology, and control of infection. the fundamental regulatory role of mirnas in a variety of biological processes s ...201728261201
mycobacterial dormancy systems and host responses in tuberculosis.tuberculosis (tb) caused by the intracellular pathogen, mycobacterium tuberculosis (mtb), claims more than 1.5 million lives worldwide annually. despite promulgation of multipronged strategies to prevent and control tb, there is no significant downfall occurring in the number of new cases, and adding to this is the relapse of the disease due to the emergence of antibiotic resistance and the ability of mtb to remain dormant after primary infection. the pathology of mtb is complex and largely attr ...201728261197
mycobacterium tuberculosis replicates within necrotic human macrophages.mycobacterium tuberculosis modulation of macrophage cell death is a well-documented phenomenon, but its role during bacterial replication is less characterized. in this study, we investigate the impact of plasma membrane (pm) integrity on bacterial replication in different functional populations of human primary macrophages. we discovered that ifn-γ enhanced bacterial replication in macrophage colony-stimulating factor-differentiated macrophages more than in granulocyte-macrophage colony-stimula ...201728242744
corrigendum to "immunogencity of antigens from mycobacterium tuberculosis self-assembled as particulate vaccines" [int. j. med. microbiol. 306 (2016) 624-632]. 201728242005
immunogenicity and therapeutic effects of a mycobacterium tuberculosis rv2190c dna vaccine in mice.tuberculosis (tb) is a major global public health problem. new treatment methods on tb are urgently demanded. in this study, mycobacterium tuberculosis (mtb) rv2190c dna vaccine was prepared and its immunogenicity and therapeutic effects were evaluated.201728241799
quantitative proteomic and phosphoproteomic analysis of h37ra and h37rv strains of mycobacterium tuberculosis.mycobacterium tuberculosis, the causative agent of tuberculosis, accounts for 1.5 million human deaths annually worldwide. despite efforts to eradicate tuberculosis, it still remains a deadly disease. the two best characterized strains of m. tuberculosis, virulent h37rv and avirulent h37ra, provide a unique platform to investigate biochemical and signaling pathways associated with pathogenicity. to delineate the biomolecular dynamics that may account for pathogenicity and attenuation of virulenc ...201728241730
essentiality of mmpl3 and impact of its silencing on mycobacterium tuberculosis gene expression.mmpl3 is an inner membrane transporter of mycobacterium tuberculosis responsible for the export of trehalose momomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (tdm), as well as mycolic acids bound to arabinogalactan. mmpl3 represents an emerging target for tuberculosis therapy. in this paper, we describe the construction and characterization of an mmpl3 knockdown strain of m. tuberculosis. downregulation of mmpl3 led to a stop in bacterial division and ...201728240248
a systematic review of east african-indian family of mycobacterium tuberculosis in brazil.the mycobacterium tuberculosis east african-indian (eai) spoligotyping family (belonging to lineage 1, indo-oceanic, defined by the region of deletion rd239) is distributed worldwide, but is more prevalent in southeast asia, india, and east africa. studies in latin america have rarely identified eai. in this study, we describe the occurrence of the eai family in brazil.201728238627
passive transfer of interferon-γ over-expressing macrophages enhances resistance of scid mice to mycobacterium tuberculosis infection.infection with mycobacterium tuberculosis (m.tb) is associated with increased deaths worldwide. alveolar macrophages (ams) play a critical role in host defense against infection with this pathogen. in this work we tested the hypothesis that passive transfer of normal ams, ifn-γ activated ams, or macrophages transduced to over-express ifn-γ into the lungs of immunosuppressed scid mice, where resident macrophages are present but not functional, would enhance alveolar immunity and increase clearanc ...201728237876
three year evaluation of xpert mtb/rif in a low prevalence tuberculosis setting: a scottish perspective.xpert mtb/rif (cepheid) is a rapid molecular assay shown to be sensitive and specific for pulmonary tuberculosis (tb) diagnosis in highly endemic countries. we evaluated its diagnostic performance in a low tb prevalence setting, examined rifampicin resistance detection and quantitative capabilities predicting graded auramine microscopy and time to positivity (ttp) of culture.201728237624
recurrent tuberculosis in an urban area in china: relapse or exogenous reinfection?recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. we conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of hiv infection. genotyping the mycobacterium tuberculosis from clinical isolates was used ...201728237039
local targeting nf-κb in the lung tissue of tb-infected mice diminishes the level of pathology.mice of the genetically tb-susceptible strain i/st were infected with ∼100 cfu of mycobacterium tuberculosis strain h37rv, and after week 3 post-infection treated by inhalations of the nbd peptide selectively blocking nf-κb activation pathway. this therapy resulted in a pronounced attenuation of lung pathology and down-regulation of the expression of several genes encoding major inflammatory molecules, but did not diminish the level of mycobacterial multiplication in the lungs.201728237038
machine learning and docking models for mycobacterium tuberculosis topoisomerase i.there is a shortage of compounds that are directed towards new targets apart from those targeted by the fda approved drugs used against mycobacterium tuberculosis. topoisomerase i (mttopo i) is an essential mycobacterial enzyme and a promising target in this regard. however, it suffers from a shortage of known inhibitors. we have previously used computational approaches such as homology modeling and docking to propose 38 fda approved drugs for testing and identified several active molecules. to ...201728237034
sclerotiorin inhibits protein kinase g from mycobacterium tuberculosis and impairs mycobacterial growth in macrophages.as a eukaryotic-like ser/thr protein kinase, mycobacterium tuberculosis virulent effector protein kinase g (pkng) mediates mycobacterial survival by regulating bacterial cell metabolic processes and preventing phagosome-lysosome fusion in host macrophages. targeting pkng is an effective strategy for development of anti-tuberculosis (tb) drugs. in the study, we found that sclerotiorin, derived from marine fungi from the south china sea, exhibited moderately strong inhibitory effects on recombinan ...201728237032
single nucleotide polymorphisms may explain the contrasting phenotypes of two variants of a multidrug-resistant mycobacterium tuberculosis strain.globally, about 4.5% of new tuberculosis (tb) cases are multi-drug-resistant (mdr), i.e. resistant to the two most powerful first-line anti-tb drugs. indeed, 480,000 people developed mdr-tb in 2015 and 190,000 people died because of mdr-tb. the mdr mycobacterium tuberculosis m family, which belongs to the haarlem lineage, is highly prosperous in argentina and capable of building up further drug resistance without impairing its ability to spread. in this study, we sequenced the whole genomes of a ...201728237031
c5ar contributes to the weak th1 profile induced by an outbreak strain of mycobacterium tuberculosis.c5a anaphylatoxin is a component of the complement system involved in the modulation of t-cell polarization. herein we investigated whether c5a receptors, c5ar and c5l2, modulate the cytokine profiles induced by mycobacterium tuberculosis (mtb). we analyzed the impact of both receptors on t helper cell polarization induced by the multidrug resistant outbreak strain named m, which is a poor ifn-γ inducer compared with the laboratory strain h37rv. to this aim, we first blocked c5ar or c5l2 of peri ...201728237029
cholesterol plays a larger role during mycobacterium tuberculosis in vitro dormancy and reactivation than previously suspected.it is known that cholesterol plays a key role for mycobacterium tuberculosis (mtb) adaptation and survival within the host, thus contributing to the establishment of dormancy. it has been extensively demonstrated that fatty acids are the main energy source of mtb during infection and dormancy, and it has been proposed that these molecules are implicated in reactivation of bacilli from a dormant state. we used in vitro models to analyze mtb gene expression during dormancy and reactivation when fa ...201728237027
evaluation of highly conserved hsp65-specific nested pcr primers for diagnosing mycobacterium tuberculosis.to evaluate the sensitivity and specificity of a new nested set of primers designed for the detection of mycobacterium tuberculosis complex targeting a highly conserved heat shock protein gene (hsp65).201728234087
endocrine and metabolic aspects of tuberculosis.endocrine and metabolic derangements are infrequent in patients with tuberculosis, but they are important when they occur. the basis for these abnormalities is complex. while mycobacterium tuberculosis has been described to infect virtually every endocrine gland, the incidence of gland involvement is low, especially in the era of effective antituberculosis therapy. furthermore, endocrine and metabolic abnormalities do not always reflect direct infection of the gland but may result from physiolog ...201728233510
targeting phenotypically tolerant mycobacterium tuberculosis.while the immune system is credited with averting tuberculosis in billions of individuals exposed to mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. in individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of m. tuberculosis. the physiological state of nonreplication in bacteria is associated w ...201728233509
[a preliminary study on the molecular characteristics of d-cycloserine resistance of mycobacterium tuberculosis].objective: to investigate the relationship between d-cycloserine resistance and the gene mutations of alra, ddla and cyca of mycobacterium (m.) tuberculosis, as well as the association between d-cycloserine resistance and spoligotyping genotyping. methods: a total of 145 m. tuberculosis strains were selected from the strain bank. d-cycloserine resistant phenotypes of the strains were determined by the proportion method and the minimal inhibitory concentration was determined by resazurin microtit ...201728231674
siderophore transport by mmpl5-mmps5 protein complex in mycobacterium tuberculosis.iron is an essential metal ion required for the various physiological activities of bacteria. the pathogenic bacteria remain dependent on the host cell for their iron requirements and evolved with specialized scavenging machinery in the form of iron chelating siderophores. mycobacterium tuberculosis has two types of siderophore molecules, mycobactin and carboxymycobactin. these are synthesized inside bacterial cells and need to be transported outside by specialized membrane associated proteins. ...201728231453
genetic diversity, transmission dynamics and drug resistance of mycobacterium tuberculosis in angola.tuberculosis (tb) poses a serious public health problem in angola. no surveillance data on drug resistance is available and nothing is known regarding the genetic diversity and population structure of circulating mycobacterium tuberculosis strains. here, we have genotyped and evaluated drug susceptibility of 89 mycobacterium tuberculosis clinical isolates from luanda. thirty-three different spoligotype profiles corresponding to 24 different shared international types (sit) and 9 orphan profiles ...201728230095
perturbed microrna expression by mycobacterium tuberculosis promotes macrophage polarization leading to pro-survival foam cell.tuberculosis (tb) is one of the prevalent causes of death worldwide, with 95% of these deaths occurring in developing countries, like india. the causative agent, mycobacterium tuberculosis (mtb) has the tenacious ability to circumvent the host's immune system for its own advantage. macrophages are one of the phagocytic cells that are central to immunity against mtb. these are highly plastic cells dependent on the milieu and can showcase m1/m2 polarization. m1 macrophages are bactericidal in acti ...201728228760
characterisation of iunh gene knockout strain from mycobacterium tuberculosis.tuberculosis (tb) is an infectious disease caused mainly by the bacillus mycobacterium tuberculosis. the better understanding of important metabolic pathways from m. tuberculosis can contribute to the development of novel therapeutic and prophylactic strategies to combat tb. nucleoside hydrolase (mtiagu-nh), encoded by iunh gene (rv3393), is an enzyme from purine salvage pathway in m. tuberculosis. mtiagu-nh accepts inosine, adenosine, guanosine, and uridine as substrates, which may point to a p ...201728225907
tuberculosis associated factors caused by mycobacterium tuberculosis of the rdrio genotype.tuberculosis (tb) continues to be a disease that affects many countries around the world, including brazil. recently, a subtype of latin american-mediterranean family strain was identified and characterised by rdrio. the strain has been associated with different characteristics of the disease.201728225901
tuberculosis associated factors caused by mycobacterium tuberculosis of the rdrio genotype.tuberculosis (tb) continues to be a disease that affects many countries around the world, including brazil. recently, a subtype of latin american-mediterranean family strain was identified and characterised by rdrio. the strain has been associated with different characteristics of the disease.201728225895
perceived barriers to adherence to tuberculosis infection control measures among health care workers in the dominican republic.introduction health care workers have an increased risk of infection due to occupational mycobacterium tuberculosis exposure, including multidrug-resistant strains. health care workers' risk of developing tuberculosis is greater than that of the general population, whether in low-, intermediate- or high-incidence countries. adherence to infection control measures (administrative controls, environmental controls, and personal respiratory protection) is essential to reduce risk of disease transmis ...201728225541
antituberculosis drug resistance in pulmonary isolates of mycobacterium tuberculosis, cuba 2012-2014.introduction systematic surveillance of antituberculosis drug resistance allows identification of multidrug-resistant and extensively drug-resistant isolates of mycobacterium tuberculosis. surveillance studies of antituberculosis drug resistance systematically conducted in cuba for over 15 years have revealed low circulation of multidrug-resistant tuberculosis, under 1% in new cases. objective characterize antituberculosis drug resistance in isolates of m. tuberculosis recovered from patients wi ...201728225540
results of xpert(®) mtb/rif implementation in kyrgyzstan.in july 2012, the united states agency for international development (usaid) quality health care project introduced the xpert® mtb/rif assay at the facility level of the primary health care system in kyrgyzstan. this study analysed the results of the implementation of xpert.201728225345
patterns of drug resistance among patients with tuberculous pleural effusion in greece.data on the relationship between pleural tuberculosis (tb) and anti-tuberculosis drug resistance are scarce.201728225341
pattern of first- and second-line drug resistance among pulmonary tuberculosis retreatment cases in pakistan.drug resistance in general, and multidrug-resistant tuberculosis (mdr-tb) in particular, threatens global tuberculosis (tb) control efforts. population-based estimates of drug resistance are needed to develop strategies for controlling drug-resistant tb in pakistan.201728225340
latent tuberculous infection in household contacts of multidrug-resistant and newly diagnosed tuberculosis.differences in the prevalence of latent tuberculous infection (ltbi) and tuberculosis (tb) disease among contacts of patients with multidrug-resistant tb (mdr-tb) and drug-susceptible tb are not well understood.201728225339
multiple cytokines for the detection of mycobacterium tuberculosis infection in children with tuberculosis.interferon-gamma (ifn-γ) release assays (igras) play an important role in the diagnosis of mycobacterium tuberculosis infection. however, in children with tuberculosis (tb), some studies have shown increased frequencies of false-negative or indeterminate igra results.201728225337
elucidating the biosynthetic pathways of volatile organic compounds in mycobacterium tuberculosis through a computational approach.microbial volatile organic compounds (vocs) have gained prominence in the recent past for their potential use as disease markers. the discovery of microbial vocs has benefited 'difficult to detect' diseases such as tuberculosis (tb). few of the identified vocs of mycobacterium tuberculosis (mtb) are currently being explored for their diagnostic potential. however, very little is known about the biosynthesis of these small lipophilic molecules. here, we propose putative biosynthetic pathways in m ...201728225105
tuberculosis.essential facts tuberculosis (tb) is an infection caused by a bacterium, mycobacterium tuberculosis. while it can affect any part of the body, only pulmonary tb is infectious. according to the charity tb alert, there were 5,758 cases of tb in the uk in 2015 and 39% of them were in london. this represented a fall from a peak of 8,919 cases in 2011. left untreated, tb is life-threatening, but is usually curable with antibiotics. the sooner it is diagnosed and treated, the better, both for the pers ...201728224849
mycobacterium tuberculosis prolyl oligopeptidase induces in vitro secretion of proinflammatory cytokines by peritoneal macrophages.tuberculosis (tb) is a disease that leads to death over 1 million people per year worldwide and the biological mediators of this pathology are poorly established, preventing the implementation of effective therapies to improve outcomes in tb. host-bacterium interaction is a key step to tb establishment and the proteases produced by these microorganisms seem to facilitate bacteria invasion, migration and host immune response evasion. we presented, for the first time, the identification, biochemic ...201728223969
secretome prediction of two m. tuberculosis clinical isolates reveals their high antigenic density and potential drug targets.the excreted/secreted (es) proteins play important roles during mycobacterium tuberculosis invasion, virulence, and survival inside the host and they are a major source of immunogenic proteins. however, the molecular complexity of the bacillus cell wall has made difficult the experimental isolation of the total bacterial es proteins. here, we reported the genomes of two beijing genotype m. tuberculosis clinical isolates obtained from patients from vietnam (isolate 46) and south africa (isolate 4 ...201728223967
rational design of adjuvants targeting the c-type lectin mincle.the advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. identification of the c-type lectin mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6'-dimycolate (tdm), has opened avenues for the rational design of such molecules. using a combination of chemical synthesis, biological evaluation, molecular dynamics si ...201728223515
mycobacterium tuberculosis proteasome accessory factor a (pafa) can transfer prokaryotic ubiquitin-like protein (pup) between substrates.the protein degradation machinery of mycobacterium tuberculosis includes a proteasome and a ubiquitin-like protein (pup). proteasome accessory factor a (pafa) attaches pup to proteins to target them for degradation by the proteasome. free pup is unstable and never observed in extracts of m. tuberculosis, an observation that led us to hypothesize that pafa may need alternative sources of pup. here, we show that pafa can move pup from one proteasome substrate, inositol 1-phosphate synthetase (ino1 ...201728223451
identification of antibody targets for tuberculosis serology using high-density nucleic acid programmable protein arrays.better and more diverse biomarkers for the development of simple point-of-care tests for active tuberculosis (tb), a clinically heterogeneous disease, are urgently needed. we generated a proteomic mycobacterium tuberculosis (mtb) high-density nucleic acid programmable protein array (hd-nappa) that used a novel multiplexed strategy for expedited high-throughput screening for antibody responses to the mtb proteome. we screened sera from hiv uninfected and coinfected tb patients and controls (n = 1 ...201728223349
functional reconstitution of the mycobacterium tuberculosis long-chain acyl-coa carboxylase from multiple acyl-coa subunits.mycobacterium tuberculosis produces a large number of structurally diverse lipids that have been implicated in the pathogenicity, persistence and antibiotic resistance of this organism. most building blocks involved in the biosynthesis of all these lipids are generated by acyl-coa carboxylases whose subunit composition and physiological roles have not yet been clearly established. inconclusive data in the literature refer to the exact protein composition and substrate specificity of the enzyme c ...201728222482
molecular epidemiology of mycobacterium tuberculosis complex in brussels, 2010-2013.the tuberculosis (tb) incidence rate in brussels-capital region is 3-fold higher than in belgium as a whole. eight years after the realization of initial prospective population-based molecular epidemiology investigations in this region, a similar study over the period 2010-2013 was conducted. tb strains isolated from 945 patients were submitted to genotyping by standardized 24-locus-miru-vntr typing and spoligotyping. the phylogenetic analysis showed that the lam (16.7%) and haarlem (15.7%) bran ...201728222189
mycobacterium tuberculosis transmission among elderly persons, yamagata prefecture, japan, 2009-2015.in many countries with low to moderate tuberculosis (tb) incidence, cases have shifted to elderly persons. it is unclear, however, whether these cases are associated with recent mycobacterium tuberculosis transmission or represent reactivation of past disease. during 2009-2015, we performed a population-based tb investigation in yamagata prefecture, japan, using in-depth contact tracing and 24-loci variable-number tandem-repeat typing optimized for beijing family m. tuberculosis strains. we anal ...201728221133
new mycobacterium tuberculosis complex sublineage, brazzaville, congo.tuberculosis is a leading cause of illness and death in congo. no data are available about the population structure and transmission dynamics of the mycobacterium tuberculosis complex strains prevalent in this central africa country. on the basis of single-nucleotide polymorphisms detected by whole-genome sequencing, we phylogenetically characterized 74 mtbc isolates from brazzaville, the capital of congo. the diversity of the study population was high; most strains belonged to the euro-american ...201728221129
mycobacterium tuberculosis infection among asian elephants in captivity.although awareness of tuberculosis among captive elephants is increasing, antituberculosis therapy for these animals is not standardized. we describe mycobacterium tuberculosis transmission between captive elephants based on whole genome analysis and report a successful combination treatment. infection control protocols and careful monitoring of treatment of captive elephants with tuberculosis are warranted.201728221115
mycobacterium tuberculosis infection in free-roaming wild asian elephant.postmortem examination of a wild asian elephant at rajiv gandhi national park, india, revealed nodular lesions, granulomas with central caseation, and acid-fast bacilli in the lungs. pcr and nucleotide sequencing confirmed the presence of mycobacterium tuberculosis. this study indicates that wild elephants can harbor m. tuberculosis that can become fatal.201728221114
pnca gene mutations associated with pyrazinamide resistance in drug-resistant tuberculosis, south africa and georgia.although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. we found polymorphisms in the pnca gene for 70% of multidrug-resistant and 96% of extensively drug-resistant mycobacterium tuberculosis isolates from south africa and georgia. assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.201728221108
mycobacterium tuberculosis in wild asian elephants, southern india.we tested 3 ild asian elephants (elephas maximus) in southern india and confirmed infection in 3 animals with mycobacterium tuberculosis, an obligate human pathogen, by pcr and genetic sequencing. our results indicate that tuberculosis may be spilling over from humans (reverse zoonosis) and emerging in wild elephants.201728221104
more significance of tb-igra except for the diagnose of tuberculosis.tuberculosis (tb)-interferon gamma release assay (igra) test has the characteristics of short time, high specificity, and high sensitivity, but it lacks the correlation research between tb-igra test results and body's immune cells, disease progression and prognosis, which is explored in this study.201728220979
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