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reversion of antibiotic resistance in mycobacterium tuberculosis by spiroisoxazoline smart-420.antibiotic resistance is one of the biggest threats to human health globally. alarmingly, multidrug-resistant and extensively drug-resistant mycobacterium tuberculosis have now spread worldwide. some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. we have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in m. tube ...201728302858
alternative quantiferon cytokines for diagnosis of children with active tuberculosis and hiv co-infection in ghana.ifn-γ release assays (igras) often present false-negative or indeterminate results in children with tuberculosis. hiv co-infection may contribute to decreased sensitivity of igras by impairing t-cell ifn-γ expression. measurement of alternative cytokines in quantiferon(®) (qft) supernatants can circumvent the ifn-γ-dependency and may improve qft sensitivity. we aimed to identify additional cytokines from qft supernatants for detection of mycobacterium tuberculosis infection in children with tube ...201728299430
effects of ifn-β1a and ifn-β1b treatment on the expression of cytokines, inducible nos (nos type ii), and myelin proteins in animal model of multiple sclerosis.the aim of this study was to investigate the effects of interferon (ifn)-β1a and ifn-β1b treatment on inflammatory factors and myelin protein levels in the brain cortex of the lewis rat experimental autoimmune encephalomyelitis (eae), animal model of multiple sclerosis. to induce eae, rat were immunized with inoculums containing spinal cord guinea pig homogenized in phosphate-buffered saline and emulsified in freund's complete adjuvant containing 110 µg of the appropriate antigen in 100 µl of an ...201728299403
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
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
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
mycobacterial musculoskeletal infections.although less common as causes of musculoskeletal infection than pyogenic bacteria, both mycobacterium tuberculosis and nontuberculous mycobacteria can infect bones and joints. although tuberculous arthritis and osteomyelitis have been recognized for millennia, infections caused by nontuberculous mycobacteria are being identified more often, likely because of a more susceptible host population and improvements in diagnostic capabilities. despite advances in modern medicine, mycobacterial infecti ...201728292541
evolutionary thrift: mycobacteria repurpose plasmid diversity during adaptation of type vii secretion systems.mycobacteria have a distinct secretion system, termed type vii (t7ss), which is encoded by paralogous chromosomal loci (esx) and associated with pathogenesis, conjugation, and metal homeostasis. evolution of paralogous gene families is of interest because duplication is an important mechanism by which novel genes evolve, but there are potential conflicts between adaptive forces that stabilize duplications and those that enable evolution of new functions. our objective was to delineate the adapti ...201728391322
isoniazid derivatives and their anti-tubercular activity.tuberculosis (tb), which has been a scourge of humanity for thousands of years, is a worldwide pandemic disease caused mainly by mycobacterium tuberculosis (mtb). the emergence of drug-resistant tb (dr-tb), multidrug-resistant tb (mdr-tb), extensively drug-resistant tb (xdr-tb) and totally drug-resistant tb (tdr-tb) increase the challenges to eliminate tb worldwide. isoniazid (inh), a critical frontline anti-tb drug, is one of the most effective drugs used to treatment of tb infection for more t ...201728390957
tuberculous posterior sclero-uveitis with features of vogt-koyanagi-harada uveitis: an unusual case.background ocular tuberculosis (tb) is a clinical entity that presents with a wide range of clinical manifestations. it is regarded as an extremely challenging condition from the point of view of diagnostic approach and calls for early diagnosis and prompt treatment, as it can potentially lead to blindness. case report this is a case report of a 32-year-old male from southern india who has been living and working in greece over the last 10 years and presented with 2-week history of pain and prog ...201728389634
rapid molecular diagnosis of the mycobacterium tuberculosis rangipo strain responsible for the largest recurring tb cluster in new zealand.despite new zealand being a low-tuberculosis (tb) burden country, there are disproportionately high rates of tb in particular populations. here, we report a rapid molecular diagnosis of the mycobacterium tuberculosis rangipo strain responsible for the largest recurring tb cluster in new zealand.201728389146
mycobacterium tuberculosis lysine-ɛ-aminotransferase a potential target in dormancy: benzothiazole based inhibitors.mtb lysine-ɛ-aminotransferase (lat) was found to play a crucial role in persistence and antibiotic tolerance. lat serves as a potential target in the management of latent tuberculosis. in present work we attempted to derivatize the benzothiazole lead identified through high throughput virtual screening of birla institute of technology and science in house database. for structure activity relationship purpose 22 derivatives were synthesized and characterized. among synthesized compounds, eight co ...201728389113
corrigendum: persisting positron emission tomography lesion activity and mycobacterium tuberculosis mrna after tuberculosis cure. 201728388609
examination of bedaquiline- and linezolid-resistant mycobacterium tuberculosis isolates from the moscow region.to study the isolates with acquired resistance to bedaquiline and linezolid that were obtained from patients enrolled in a clinical study of a novel therapy regimen for drug-resistant tb in moscow, russia.201728387862
the sec pathways and exportomes of mycobacterium tuberculosis.all bacteria utilize pathways to export proteins from the cytoplasm to the bacterial cell envelope or extracellular space. many exported proteins function in essential physiological processes or in virulence. consequently, the responsible protein export pathways are commonly essential and/or are important for pathogenesis. the general sec protein export pathway is conserved and essential in all bacteria, and it is responsible for most protein export. the energy for sec export is provided by the ...201728387178
in vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates.tuberculosis is caused by mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. an increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. the cellular uptake of the antimycobacterial agents by infected host cells is limited. our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an incre ...201728384546
sustained elevated levels of c-reactive protein and ferritin in pulmonary tuberculosis patients remaining culture positive upon treatment initiation.clinical trials that evaluate new anti-tubercular drugs and treatment regimens take years to complete due to the slow clearance of mycobacterium tuberculosis infection and the lack of early biomarkers that predict treatment outcomes. host inflammation markers have been associated with tuberculosis (tb) pathogenesis. in the present study, we tested if circulating levels of c-reactive protein (crp) and ferritin reflect mycobacterial loads and inflammation in pulmonary tb (ptb) patients undergoing ...201728384354
correction: hypervirulent mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant c57bl/6 mice.[this corrects the article doi: 10.1371/journal.pone.0173715.].201728384318
trehalose dimycolate interferes with fcγr-mediated phagosome maturation through mincle, shp-1 and fcγriib signalling.the causative agent of tuberculosis, mycobacterium tuberculosis (m. tuberculosis), contains an abundant cell wall glycolipid and a crucial virulence factor, trehalose-6,6'-dimycolate (tdm). tdm causes delay of phagosome maturation and thus promotes survival of mycobacteria inside host macrophages by a not fully understood mechanism. tdm signals through the monocyte-inducible c-type lectin (mincle), a recently identified pattern recognition receptor. here we show that recruitment of mincle by tdm ...201728384255
comprehensive whole-genome sequencing and reporting of drug resistance profiles on clinical cases of mycobacterium tuberculosis in new york state.whole-genome sequencing (wgs) is a newer alternative for tuberculosis (tb) diagnostics, capable of providing rapid drug resistance profiles while performing species identification and capturing the data necessary for genotyping. our laboratory developed and validated a comprehensive and sensitive wgs assay to characterize mycobacterium tuberculosis and other m. tuberculosis complex (mtbc) strains, comprised of a novel dna extraction, optimized library preparation, paired-end wgs, and an in-house ...201728381603
evaluation of the microscopic observation drug susceptibility assay for the detection of first- and second-line drug susceptibility for mycobacterium tuberculosis. 201728381434
selective amplification of spr biosensor signal for recognition of rpob gene fragments by use of gold nanoparticles modified by thiolated dna.an experimental approach for improving the sensitivity of the surface plasmon resonance (spr) dna hybridization sensor using gold nanoparticles (gnps), modified by specific oligonucleotides, was elaborated. an influence of the ionic strength on the aggregation stability of unmodified gnps and gnps modified by the thiolated oligonucleotides was investigated by monitoring a value of light extinction at 520 nm that can be considered as a measure of a quantity of the non-aggregated gnps. while the u ...201728381076
microscopic observation drug-susceptibility assay vs xpert(®) mtb/rif for the diagnosis of tuberculosis in a rural african setting: a cost-utility analysis.to compare the cost-utility of microscopic observation drug-susceptibility assay (mods) and xpert(®) mtb/rif implementation for tb diagnosis in rural northern mozambique.201728380276
investigation of the mycobacterial enzyme hsad as a potential novel target for anti-tubercular agents using a fragment-based drug design approach.with the emergence of extensively drug-resistant tuberculosis there is a need for new anti-tubercular drugs that work through novel mechanisms of action. the meta cleavage product hydrolase, hsad, has been demonstrated to be critical to the survival of mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in m. tuberculosis and m. bovis bcg.201728380256
field evaluation of a blood based test for active tuberculosis in endemic settings.over 9 million new active tuberculosis (tb) cases emerge each year from an enormous pool of 2 billion individuals latently infected with mycobacterium tuberculosis (m. tb.) worldwide. about 3 million new tb cases per year are unaccounted for, and 1.5 million die. tb, however, is generally curable if diagnosed correctly and in a timely manner. the current diagnostic methods for tb, including state-of-the-art molecular tests, have failed in delivering the capacity needed in endemic countries to cu ...201728380055
mycobacterium tuberculosis in central ethiopia: drug sensitivity patterns and association with genotype.drug resistance tuberculosis (tb) and the emergence of multidrug resistant (mdr) isolates are significant concerns regarding tb control programs in several countries. this study was undertaken to evaluate the drug sensitivity of mycobacterium tuberculosis and to assess its association with strains and lineages of m. tuberculosis. a total of 279 m. tuberculosis strains isolated from central ethiopia were tested for their drug sensitivity patterns to first line tb drugs using the conventional prop ...201728377803
m. tuberculosis hypothetical proteins and proteins of unknown function: hope for exploring novel resistance mechanisms as well as future target of drug resistance.drug resistance in tuberculosis predominantly, mono-resistance, multi drug resistance, extensively drug resistance and totally drug resistance have emerged as a major problem in the chemotherapy of tuberculosis. failures of first and second line anti-tuberculosis drugs treatment leads to emergence of resistant mycobacterium tuberculosis. few genes are reported as the principal targets of the resistance and apart from the primary targets many explanations have been proposed for drug resistance bu ...201728377758
mycobacterium tuberculosis in solid organ transplantation: incidence before and after expanded isoniazid prophylaxis.the risk of tuberculosis is increased in solid organ transplantation. rates remain high in developed and developing countries. we developed protocols to better identify transplant recipients at risk of tuberculosis and initiate interventions to prevent tuberculosis.201728377543
papers of note in science immunology2 (9).this month's articles show how an anti-inflammatory mediator is required for allergic responses, how targeting of the deacetylase sirtuin 1 may provide a therapy against mycobacterium tuberculosis infection, and how an inhibitory receptor limits the proliferation of regulatory t cells in autoimmune diabetes.201728377410
insights into substrate modification by dehydratases from type i polyketide synthases.dehydration reactions play a crucial role for de novo biosynthesis of fatty acids and a wide range of pharmacologically active polyketide natural products with strong emphasis in human medicine. the type i polyketide synthase ppsc from mycobacterium tuberculosis catalyzes key biosynthetic steps of lipid virulence factors phthiocerol dimycocerosates (dim) and phenolic glycolipids (pgl). given the insolubility of the natural c28-c30 fatty acyl substrate of the ppsc dh domain, we investigated its s ...201728377293
immunological response to mycobacterium tuberculosis infection in blood from type 2 diabetes patients.the convergence of tuberculosis and diabetes represents a co-epidemic that threatens progress against tuberculosis. we have investigated type 2 diabetes as a risk factor for tuberculosis susceptibility, and have used as experimental model whole blood infected in vitro with mycobacterium tuberculosis. blood samples from diabetic patients were found to have a higher absolute neutrophil count that non-diabetic controls, but their immune functionality seemed impaired because they displayed a lower c ...201728377108
using structural knowledge in the protein data bank to inform the search for potential host-microbe protein interactions in sequence space: application to mycobacterium tuberculosis.a comprehensive map of the human-m. tuberculosis (mtb) protein interactome would help fill the gaps in our understanding of the disease, and computational prediction can aid and complement experimental studies towards this end. several sequence-based in silico approaches tap the existing data on experimentally validated protein-protein interactions (ppis); these ppis serve as templates from which novel interactions between pathogen and host are inferred. such comparative approaches typically mak ...201728376709
spoligotyping of mycobacterium tuberculosis isolates at a tertiary care hospital in india.spoligotyping is a valuable genotyping tool to study the genetic diversity and molecular epidemiology of mycobacterium tuberculosis (m. tb). the aim of this study was to analyse different spoligotype patterns of m. tb strains isolated from tuberculosis patients from different parts of india.201728374900
association of esat-6/cfp-10-induced ifn-γ, tnf-α and il-10 with clinical tuberculosis: evidence from cohorts of pulmonary tuberculosis patients, household contacts, and community controls in an endemic setting.mycobacterium tuberculosis (mtb) early secreted protein antigen 6 (esat-6) and culture filtrate protein 10 (cfp-10) are among candidate vaccines against tuberculosis (tb). results of experimental animal models show that these antigens are associated with induction of strong t cell immunity (ifn-γ production), while others report that these proteins as virulent factors involved in pathogenicity of mtb infection. however, the role of esat-6/cfp-10 during natural mtb infections in humans has not be ...201728374535
mycobacterium tuberculosis cell wall fragments released upon bacterial contact with the human lung mucosa alter the neutrophil response to infection.in 2016, the world health organization reported that one person dies of tuberculosis (tb) every 21 s. a host environment that mycobacterium tuberculosis (m.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. we published that human lung mucosa, or alveolar lining fluid (alf), contains an array of hydrolytic enzymes that can significantly alter the m.tb surface during infection by cleaving off parts of its cell wall. t ...201728373877
biosafety level 3 setup for multiphoton microscopy in vivo.multiphoton microscopy has revealed important insights into cellular behavior in vivo. however, its application in infectious settings often encounters technical, safety and regulatory limitations that prevent its wider use with highly virulent human pathogens. herein, we present a method that renders multiphoton microscopy in vivo compatible with biosafety level 3 regulations and present an example of its application and potential to visualize a mycobacterium tuberculosis infection of the mouse ...201728373723
titration of trace amounts of immunoglobulins in a microarray-based assay with magnetic labels.the existing immunoassay format that combines the electrophoretic collection of charged analytes on an antibody microarray with the detection of the bound analytes by magnetic beads coated with secondary antibodies displays extreme sensitivity and speed, but suffers from low precision because of high signal scatter and low signal-to-concentration ratio. here we report three innovations that substantially improve the precision of this method and enable quantitative measurements of analyte concent ...201728372726
chemistry and redox biology of mycothiol.mycothiol (msh, accys-glcn-ins) is the main low molecular weight thiol of most actinomycetes, including the human pathogen mycobacterium tuberculosis that affects millions of people worldwide. strains with decreased msh content show increased susceptibilities to hydroperoxides and electrophilic compounds. in m. tuberculosis, msh modulates the response to several anti-tuberculosis drugs. enzymatic routes involving msh could provide clues for specific drug design. recent advances. physico-chemical ...201728372502
the influence of hiv on the evolution of mycobacterium tuberculosis.hiv significantly affects the immunological environment during tuberculosis co-infection, and therefore may influence the selective landscape upon which m. tuberculosis evolves. to test this hypothesis whole genome sequences were determined for 169 south african m. tuberculosis strains from hiv-1 co-infected and uninfected individuals and analysed using two bayesian codon-model based selection analysis approaches: fubar which was used to detect persistent positive and negative selection (selecti ...201728369607
antimicrobial resistance in mycobacterium tuberculosis: mechanistic and evolutionary perspectives.antibiotic-resistant mycobacterium tuberculosis strains are threatening progress in containing the global tuberculosis epidemic. mycobacterium tuberculosis is intrinsically resistant to many antibiotics, limiting the number of compounds available for treatment. this intrinsic resistance is due to a number of mechanisms including a thick, waxy, hydrophobic cell envelope and the presence of drug degrading and modifying enzymes. resistance to the drugs which are active against m. tuberculosis is, i ...201728369307
galectins and trims directly interact and orchestrate autophagic response to endomembrane damage.macroautophagy/autophagy is a homeostatic process delivering cytoplasmic targets, including damaged organelles, to lysosomes for degradation; however, it is not completely understood how compromised endomembranes are recognized by the autophagic apparatus. we have previously described that the trim family of proteins act as receptors for selective autophagy. in this study we uncovered the property of trims to directly interact with members of the family of cytosolic lectins termed galectins. gal ...201728368693
role of multiplex polymerase chain reaction in diagnosing tubercular meningitis.tuberculous meningitis (tbm) is one of the most serious manifestations of extrapulmonary tuberculosis. timely and accurate diagnosis provides a favorable prognosis in patients with tbm. the study evaluated the use of multiplex polymerase chain reaction (pcr) in the diagnosis of tbm. a study was conducted on 74 patients clinically suspected with tbm. the cerebrospinal fluid (csf) specimens were processed for smear microscopy, middle brook 7h9 culture, and multiplex pcr using primers directed agai ...201728367034
immune-related gene polymorphisms in pulmonary diseases.between the dna sequences of two randomly-selected human genomes, which consist of over 3 billion base pairs and twenty five thousand genes, there exists only 0.1% variation and 99.9% sequence identity. during the last couple of decades, extensive genome-wide studies have investigated the association between single-nucleotide polymorphisms (snps), the most common dna variations, and susceptibility to various diseases. because the immune system's primary function is to defend against myriad infec ...201728366820
a high content microscopy assay to determine drug activity against intracellular mycobacterium tuberculosis.tuberculosis is one of the infectious diseases with the greatest global burden, affecting millions of people. the rise of multi- and extensively- drug resistant forms of mycobacterium tuberculosis over the last few decades has highlighted the urgent need for development of new drugs to treat the disease. many drug development pipelines are based on in vitro assays examining a compound's effect on m. tuberculosis alone. these do not account for the effect of a compound on mammalian cells nor the ...201728366666
integrating lung physiology, immunology, and tuberculosis.lungs are directly exposed to the air, have enormous surface area, and enable gas exchange in air-breathing animals. they are constantly 'attacked' by microbes from both outside and inside and thus possess a unique, highly regulated local immune defense system which efficiently allows for microbial clearance while minimizing damaging inflammatory responses. as a prototypic host-adapted airborne pathogen, mycobacterium tuberculosis traverses the lung and has several 'interaction points' (ips) whi ...201728366292
evaluation of the antimicrobial activity of cationic polymers against mycobacteria: toward antitubercular macromolecules.antimicrobial resistance is a global healthcare problem with a dwindling arsenal of usable drugs. tuberculosis, caused by mycobacterium tuberculosis, requires long-term combination therapy and multi- and totally drug resistant strains have emerged. this study reports the antibacterial activity of cationic polymers against mycobacteria, which are distinguished from other gram-positive bacteria by their unique cell wall comprising a covalently linked mycolic acid-arabinogalactan-peptidoglycan comp ...201728365981
diagnostic performance of tuberculosis-specific igg antibody profiles in patients with presumptive tuberculosis from two continents.development of rapid diagnostic tests for tuberculosis is a global priority. a whole proteome screen identified mycobacterium tuberculosis antigens associated with serological responses in tuberculosis patients. we used world health organization (who) target product profile (tpp) criteria for a detection test and triage test to evaluate these antigens.201728362937
a high-throughput compatible assay to evaluate drug efficacy against macrophage passaged mycobacterium tuberculosis.the early drug development process for anti-tuberculosis drugs is hindered by the inefficient translation of compounds with in vitro activity to effectiveness in the clinical setting. this is likely due to a lack of consideration for the physiologically relevant cellular penetration barriers that exist in the infected host. we recently established an alternative infection model that generates large macrophage aggregate structures containing densely packed m. tuberculosis (mtb) at its core, which ...201728362407
therapy of multidrug-resistant and extensively drug-resistant tuberculosis.the global epidemic of multidrug-resistant tuberculosis (mdr-tb) caused by mycobacterium tuberculosis strains resistant to at least isoniazid and rifampin was recently reported as larger than previously estimated, with at least 580,000 new cases reported in 2015. extensively drug-resistant tuberculosis (xdr-tb), mdr-tb with additional resistance to a second-line fluoroquinolone and injectable, continues to account for nearly 10% of mdr cases globally. cases in india, china, and the russian feder ...201728361737
dna replication in mycobacterium tuberculosis.faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. for an obligate pathogen such as mycobacterium tuberculosis that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environ ...201728361736
assess drug resistance pattern and genetic profile of mycobacterium tuberculosis clinical isolates by molecular typing methods using direct repeats and is6110 in pulmonary tuberculosis cases.tuberculosis (tb), a highly contagious disease that sees no gender, age, or race is mainly a disease of lungs. according to world health organization, a tb patient can be completely cured with 6-9 months of anti-tb treatment under directly observed treatment short course.201728360464
discovery of a new mycobacterium tuberculosis thymidylate synthase x inhibitor with a unique inhibition profile.tuberculosis (tb), mainly caused by mycobacterium tuberculosis (mtb), is an infection that is responsible for roughly 1.5 million deaths per year. the situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. as a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. targeting the de novo synthesis of thymidylate (dtmp) is an i ...201728359706
diagnosis and treatment of drug-resistant tuberculosis.in the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. the diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. these guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, fr ...201728359606
gold - old drug with new potentials.research into gold-based drugs for a range of human diseases has seen a revival in recent years. this article reviews the most important applications of gold products in the different fields of human pathology. au(i) and au(iii) compounds have been re-introduced in clinical practice for targeting the cellular components involved in the onset and progression of viral and parasitic diseases, rheumatoid arthritis and cancer. this review, after some brief historical notes, takes into account the app ...201728359231
migration of small ligands in globins: xe diffusion in truncated hemoglobin n.in heme proteins, the efficient transport of ligands such as no or o2 to the binding site is achieved via ligand migration networks. a quantitative assessment of ligand diffusion in these networks is thus essential for a better understanding of the function of these proteins. for this, xe migration in truncated hemoglobin n (trhbn) of mycobacterium tuberculosis was studied using molecular dynamics simulations. transitions between pockets of the migration network and intra-pocket relaxation occur ...201728358830
advancing host-directed therapy for tuberculosis.tuberculosis (tb) drug-development strategies, a wide range of candidate host-directed therapies (hdt)s-including new and repurposed drugs, biologics, and cellular therapies-have been proposed to accelerate eradication of infection and overcome the problems associated with current treatment regimens. by investigating the interaction between macrophages and the intracellular parasite toxoplasma gondii (t. gondii), we uncovered that infection-induced signaling pathways suggest possibilities for th ...201728357397
insights gained from ancient biomolecules into past and present tuberculosis-a personal perspective.ancient and historical tuberculosis (tb) can be recognized by its typical paleopathology in human remains. using paleomicrobiology, it is possible to detect many more individuals infected with tb but with no visible lesions. due to advances in molecular analysis over the past two decades, it is clear that tb was widespread in humans from the neolithic period and has remained so until the present day. past human populations were associated with different lineages of the mycobacterium tuberculosis ...201727915106
antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2h-chromene and coumarin scaffold.this study reports the synthesis of new 2h-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain mycobacterium tuberculosis h37rv and compared to the first-line antituberculosis drugs, isoniazid (inh) and ethambutol (emb). the most active compounds 7m (mic 0.13μm), 7o (mic 0.15μm) and 7k (mic 0.17μm) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytoto ...201727914798
maternal bcg scar is associated with increased infant proinflammatory immune responses.prenatal exposures such as infections and immunisation may influence infant responses. we had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on bcg vaccine-induced responses in ugandan infants.201727914741
new insights into the sar and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against mycobacterium tuberculosis.2-(quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of mycobacterium tuberculosis (mtb) growth. herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (mic) values against drug-susceptible and drug-resistant mycobacterium tuberculosis strains in the submicromolar range. furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they s ...201727914363
effects of increasing the affinity of card for rna polymerase on mycobacterium tuberculosis growth, rrna transcription, and virulence.card is an essential rna polymerase (rnap) interacting protein in mycobacterium tuberculosis that stimulates formation of rnap-promoter open complexes. card plays a complex role in m. tuberculosis growth and virulence that is not fully understood. therefore, to gain further insight into the role of card in m. tuberculosis growth and virulence, we determined the effect of increasing the affinity of card for rnap. using site-directed mutagenesis guided by crystal structures of card bound to rnap, ...201727920294
divergent functions of tlr2 on hematopoietic and nonhematopoietic cells during chronic mycobacterium tuberculosis infection.we have reported that tlr2 is crucial for host resistance against chronic mycobacterium tuberculosis infection; however, which cell types are key players in this response remain unknown. this led us to decipher the relative contribution of tlr2 on nonhematopoietic and hematopoietic cells in resistance against chronic m. tuberculosis infection in mice infected with m. tuberculosis erdman. consistent with our previous report, at 8 wk of infection, tlr2 knockout (tlr2ko)→tlr2ko bone marrow chimeric ...201727920273
genotyping and prevalence of pyrazinamide- and moxifloxacin-resistant tuberculosis in china, 2000 to 2010.we investigated the prevalence, trends, and risk factors for pyrazinamide (pza) and moxifloxacin (mox) resistance among tuberculosis (tb) cases in china and also analyzed the population structure of mycobacterium tuberculosis strains. all the m. tuberculosis strains enrolled in this study were collected from the national tb prevalence surveys. each strain was genotyped by analyzing the regions of rd105 and is6110 in the ntf region. the bactec mgit 960 system was used to detect the drug susceptib ...201727919887
performance evaluation of xpert mtb/rif in a moderate tuberculosis incidence compared with taqman mtb and trcrapid m.tb.xpert mtb/rif is an automated nucleic acid amplification test (nat) that can detect the presence of mycobacterium tuberculosis complex (mtc) in clinical specimens as well as rifampicin (rif) resistance resulting from rpob mutation. despite its high sensitivity and specificity for diagnosing tuberculosis (tb) with or without rif resistance, the clinical performance of the test is variable. in this study, we evaluated the performance of xpert mtb/rif in a setting of moderate tb burden and high med ...201727919693
transmission of multidrug-resistant mycobacterium tuberculosis in shanghai, china: a retrospective observational study using whole-genome sequencing and epidemiological investigation.multidrug-resistance is a substantial threat to global elimination of tuberculosis. understanding transmission patterns is crucial for control of the disease. we used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (mdr) tuberculosis and identify potential risk factors for transmission.201727919643
intestinal pneumatosis associated with tuberculosis after allogeneic hematopoietic stem cell transplantation.pneumatosis intestinalis (pi), defined as intestinal intra- and extramural gas accumulation, is a rare radiographic finding in conditions of intestinal wall damage of varied etiology. here, we report on a 56-year-old female with multiple myeloma who presented with undulating fever, fluctuating abdominal symptoms, and a distended abdomen 5 months after allogeneic hematopoietic stem cell transplantation (hsct). abdominal x-ray and ct scan documented pi with gas accumulation both in the intestinal ...201727923223
structural characterization and ligand/inhibitor identification provide functional insights into the mycobacterium tuberculosis cytochrome p450 cyp126a1.the mycobacterium tuberculosis h37rv genome encodes 20 cytochromes p450, including p450s crucial to infection and bacterial viability. many m. tuberculosis p450s remain uncharacterized, suggesting that their further analysis may provide new insights into m. tuberculosis metabolic processes and new targets for drug discovery. cyp126a1 is representative of a p450 family widely distributed in mycobacteria and other bacteria. here we explore the biochemical and structural properties of cyp126a1, inc ...201727932461
official american thoracic society/infectious diseases society of america/centers for disease control and prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.individuals infected with mycobacterium tuberculosis (mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [ltbi]). tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain.201727932390
risk of incident mycobacterium tuberculosis infection in patients with inflammatory bowel disease: a nationwide population-based study in south korea.the low incidence of mycobacterium tuberculosis infection and lack of adequate controls have prevented researchers from estimating tuberculosis (tb) risk in inflammatory bowel disease (ibd) patients.201727933686
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