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use of genexpert remnants for drug resistance profiling and molecular epidemiology of tuberculosis in libreville, gabon.multidrug-resistant (mdr) and extensively drug resistant (xdr) strains of mycobacterium tuberculosis pose major problems for global health. the genexpert mtb/rif (xpert) assay rapidly detects resistance to rifampin (rif(r)), but for detection of the additional resistance that defines mdr-tb (mdr tuberculosis) and xdr-tb, and for molecular epidemiology, specimen cultures and a biosafe infrastructure are generally required. we sought to determine whether the remnants of sputa prepared for the xper ...201728446574
distinct prevalence of drug-resistant tuberculosis in gansu, china: a retrospective study on drug susceptibility profiles between 2010 and 2014.limited knowledge is available on regional distribution of antituberculosis (tb) drug resistance and on province-specific time-trends in tb drug susceptibility in china. to obtain the latest information about the dynamics of drug-resistant tb in gansu province, we conducted a retrospective study and analyzed data on drug resistance among new tb cases diagnosed between june 2010 and may 2014 in gansu, china. the data were collected from the only tb surveillance and treatment hospital in gansu and ...201728445109
current approaches and future prospects of nanomedicines in tuberculosis therapy.tuberculosis (tb), which is caused by the mycobacterium tuberculosis, is a serious threat and one of the major health problems worldwide. in recent years, an estimated of 9.6 million tb cases occurred and 1.5 million death occurred due to tb worldwide. the present review is an attempt to introduce this disease focusing on the pathophysiology of the disease, the current approachesand the related patents for treatment and the future planningfor combating this disease.201728443511
evaluation of a new ifn-γ release assay for rapid diagnosis of active tuberculosis in a high-incidence setting.blood-based interferon-gamma (ifn-γ) release assays (igras) have been proven to be useful in the diagnosis of mycobacterium tuberculosis (mtb) infection. however, igras have not been recommended for clinical practice in most low-income settings due to cost-intensive limitations and shortage of clinical data available. the established t-spot. tb assay containing mtb-specific antigens esat-6 and cfp10 are widely used for immunodiagonsis of mtb infection, but the high cost is one of the restricting ...201728443247
estimating tuberculin skin test reactions among children and teenagers who received the bacillus calmette-guerin vaccination at birth: a meta-analysis.tuberculin skin reaction size is one indicator of bacillus calmette-guérin (bcg) vaccine efficacy and a way to diagnose latent infection. several primary studies have examined this issue. combining the results of these studies using a meta-analysis will provide reliable evidence regarding this indicator for policymakers. this study aimed to estimate the total frequency of different tuberculin skin test reactions among iranian children and teenagers who received the bcg vaccination at birth.201728443219
the exit strategy: an approach for identifying bacterial proteins exported during host infection.exported proteins of bacterial pathogens function both in essential physiological processes and in virulence. past efforts to identify exported proteins were limited by the use of bacteria growing under laboratory (in vitro) conditions. thus, exported proteins that are exported only or preferentially in the context of infection may be overlooked. to solve this problem, we developed a genome-wide method, named exit (exported in vivotechnology), to identify proteins that are exported by bacteria d ...201728442606
complex multifractal nature in mycobacterium tuberculosis genome.the mutifractal and long range correlation (c(r)) properties of strings, such as nucleotide sequence can be a useful parameter for identification of underlying patterns and variations. in this study c(r) and multifractal singularity function f(α) have been used to study variations in the genomes of a pathogenic bacteria mycobacterium tuberculosis. genomic sequences of m. tuberculosis isolates displayed significant variations in c(r) and f(α) reflecting inherent differences in sequences among iso ...201728440326
latently and uninfected healthcare workers exposed to tb make protective antibodies against mycobacterium tuberculosis.the role of igs in natural protection against infection by mycobacterium tuberculosis (mtb), the causative agent of tb, is controversial. although passive immunization with mabs generated against mycobacterial antigens has shown protective efficacy in murine models of infection, studies in b cell-depleted animals only showed modest phenotypes. we do not know if humans make protective antibody responses. here, we investigated whether healthcare workers in a beijing tb hospital-who, although expos ...201728438994
pyrazinoic acid inhibits a bifunctional enzyme in mycobacterium tuberculosis.pyrazinamide (pza), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. while the mechanism of activation of this prodrug into pyrazinoic acid (poa) by mycobacterium tuberculosis has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. here, we report how a new pza resistance determinant, the asp67asn substitution in rv2783, confers m. tuberculosis resistance to pza. expression of th ...201728438933
effects on the qt interval of a gatifloxacin-containing regimen versus standard treatment of pulmonary tuberculosis.the effects on ventricular repolarization-recorded on the electrocardiogram (ecg) as lengthening of the qt interval-of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. a correction factor (qtc) is introduced to make the qt independent of the heart rate, translating into the slope of the regression line between qt and heart rate being close to zero. ecgs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) ...201728438924
convenient pcr method for variable-number tandem-repeat typing of mycobacterium tuberculosis clinical isolates.variable-number tandem-repeat typing for mycobacterium tuberculosis clinical isolates contributes to evidence-based tuberculosis control. however, cumbersome pcr procedures for the typing have disturbed routine analyses. we proposed a convenient pcr method for the typing using a pcr master mix that provides rapidity and long-term stability of the frozen pcr cocktail.201728438643
isolated splenic tuberculosis with subsequent paradoxical deterioration: a case report.isolated tuberculosis of the spleen has been described occasionally in literature, mostly in immunosuppressed individuals with various risk factors. sequestration in the spleen makes such mycobacterium tuberculosis infection difficult to diagnose. this report describes an extremely rare case of isolated splenic tuberculosis in an immunocompetent individual.201728438221
early detection of multidrug- and pre-extensively drug-resistant tuberculosis from smear-positive sputum by direct sequencing.emergence of multidrug- and extensively drug-resistant tuberculosis (m/xdr-tb) is a major hurdle for tb control programs especially in developing countries like china. resistance to fluoroquinolones is high among mdr-tb patients. early diagnosis of mdr/pre-xdr-tb is essential for lowering transmission of drug-resistant tb and adjusting the treatment regimen.201728438132
reproducibility of african giant pouched rats detecting mycobacterium tuberculosis.african pouched rats sniffing sputum samples provided by local clinics have significantly increased tuberculosis case findings in tanzania and mozambique. the objective of this study was to determine the reproducibility of rat results.201728438117
an attenuated mycobacterium tuberculosis clinical strain with a defect in esx-1 secretion induces minimal host immune responses and pathology.although mycobacterium tuberculosis (m.tb) dk9897 is an attenuated strain, it was isolated from a patient with extrapulmonary tuberculosis and vaccination with a subunit vaccine (h56) induced poor protection against it. both attenuation and lack of protection are because m.tb dk9897 cannot secrete the esxa virulence factor nor induce a host response against it. genome sequencing identified a frameshift mutation in the eccca1 gene. since the encoded eccca1 protein provides energy for esx-1 secret ...201728436493
functional, thermodynamics, structural and biological studies of in silico-identified inhibitors of mycobacterium tuberculosis enoyl-acp(coa) reductase enzyme.novel chemotherapeutics agents are needed to kill mycobacterium tuberculosis, the main causative agent of tuberculosis (tb). the m. tuberculosis 2-trans-enoyl-acp(coa) reductase enzyme (mtinha) is the druggable bona fide target of isoniazid. new chemotypes were previously identified by two in silico approaches as potential ligands to mtinha. the inhibition mode was determined by steady-state kinetics for seven compounds that inhibited mtinha activity. dissociation constant values at different te ...201728436453
il-10 down-regulates the expression of survival associated gene hspx of mycobacterium tuberculosis in murine macrophage.mycobacterium tuberculosis (mtb) adopts a special survival strategy to overcome the killing mechanism(s) of host immune system. amongst the many known factors, small heat shock protein 16.3 (shsp16.3) of mtb encoded by gene hspx has been reported to be critical for the survival of mtb. in the present study, the effect of recombinant murine interferon-gamma (rmifn-γ) and recombinant murine interleukin-10 (rmil-10) on the expression of gene hspx of mtb in murine macrophage raw264.7 has been invest ...201728435012
defining a research agenda to address the converging epidemics of tuberculosis and diabetes: part 2: underlying biologic mechanisms.there is growing interest in the re-emerging interaction between type 2 diabetes (dm) and tb, but the underlying biologic mechanisms are poorly understood despite their possible implications in clinical management. experts in epidemiologic, public health, basic science, and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-occurrence of tb and dm. we identified gaps in current knowledge of altered immunity in patients with ...201728434937
distant phe345 mutation compromises the stability and activity of mycobacterium tuberculosis isocitrate lyase by modulating its structural flexibility.isocitrate lyase (icl), a potential anti-tubercular drug target, catalyzes the first step of the glyoxylate shunt. in the present investigation, we studied the conformational flexibility of mtbicl to better understand its stability and catalytic activity. our biochemical results showed that a point mutation at phe345, which is topologically distant (>10 å) to the active site signature sequence ((189)kkcgh(193)), completely abolishes the activity of the enzyme. in depth computational analyses wer ...201728432345
mycobacterium tuberculosis lineage distribution in xinjiang and gansu provinces, china.mycobacterium tuberculosis (m. tuberculosis) genotyping has dramatically improved the understanding of the epidemiology of tuberculosis (tb). in this study, 187 m. tuberculosis isolates from xinjiang uygur autonomous region (xinjiang) and gansu province in china were genotyped using large sequence polymorphisms (lsps) and variable number tandem repeats (vntr). ten isolates, which represent major nodes of vntr-based minimum spanning tree, were selected and subsequently subjected to multi-locus se ...201728432321
suppressors of cytokine signaling in tuberculosis.tuberculosis (tb), a global disease mainly infected by mycobacterium tuberculosis, remains leading public health problem worldwide. suppressors of cytokine signaling (socss) play important roles in the protection against microbial infection. however, the relationship between members of the socs family and tuberculosis infection remains unclear. using peripheral blood mononuclear cells, we investigated the mrna expression profiles of socs subfamilies among active tb, latent tuberculosis infection ...201728430824
diagnosis of smear-negative tuberculosis is greatly improved by xpert mtb/rif.diagnosis of pulmonary (ptb) and extra-pulmonary tuberculosis (eptb) in smear-negative patients can be difficult. we assessed retrospectively the performance of xpert mtb/rif system (xpert, cepheid) in diagnosing smear-negative tuberculosis (tb), which represents the most common form of tb in a low incidence setting.201728430807
bedaquiline susceptibility test for totally drug-resistant tuberculosis mycobacterium tuberculosis.this study aimed to provide information that bedaquilline is significantly effective for treatment of totally drug resistant (tdr) mycobacterium tuberculosis that shows resistant to all first- and second-line drugs-using an innovative disc agarose channel (dac) system. time-lapse images of single bacterial cells under culture conditions with different concentrations of bedaquiline were analysed by image processing software to determine minimum inhibitory concentrations (mics). bedaquiline inhibi ...201728429168
dihydrolipoamide dehydrogenase-lpd (rv0462)-specific t cell recall responses are higher in healthy household contacts of tb: a novel immunodominant antigen from m. tuberculosis.the partial effectiveness against pulmonary tuberculosis (ptb), displayed by the existing tuberculosis (tb) vaccine, bacillus calmette-guérin (bcg), highlights the need for novel vaccines to replace or improve bcg. in tb immunology, antigen-specific cellular immune response is frequently considered indispensable. latency-associated antigens are intriguing as targets for tb vaccine development. the mycobacterial protein, dihydrolipoamide dehydrogenase (lpd; rv0462), the third enzyme of the pyruva ...201728428201
novel and revisited approaches in antituberculosis drug discovery.the increasing prevalence of multidrug-resistant mycobacterium tuberculosis (mtb) necessitates the discovery and development of novel drugs against tuberculosis. in this review, we focus on two recent approaches that led to the discovery of promising antitubercular compound classes: (i) hits derived from large compound library screens are increasingly difficult to translate into clinical application; this in turn fostered the development of innovative screening methods. (ii) an alternative strat ...201728427007
rapid detection of mycobacterium tuberculosis and rifampicin resistance in extrapulmonary tuberculosis and sputum smear-negative pulmonary suspects using xpert mtb/rif.tuberculosis (tb) is a serious public health problem in developing countries such as pakistan. rapid diagnosis of tb and detection of drug resistance are very important for timely and appropriate management of multidrug-resistant tb (mdr-tb).201728425873
mycobacterium tuberculosis resistance prediction and lineage classification from genome sequencing: comparison of automated analysis tools.whole-genome sequencing (wgs) has the potential to accelerate drug-susceptibility testing (dst) to design appropriate regimens for drug-resistant tuberculosis (tb). several recently developed automated software tools promise to standardize the analysis and interpretation of wgs data. we assessed five tools (castb, kvarq, mykrobe predictor tb, phyresse, and tbprofiler) with regards to dst and phylogenetic lineage classification, which we compared with phenotypic dst, sanger sequencing, and tradit ...201728425484
data intensive genome level analysis for identifying novel, non-toxic drug targets for multi drug resistant mycobacterium tuberculosis.we report the construction of a novel systems biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in mycobacterium tuberculosis (mtb). this is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. in the 1623 sequenced mtb strains, 890 metabolic genes identified through a systems approach in mtb were evaluated for non-synonymous mutations. the 33 genes showed none or one variation in the e ...201728425478
interactions between type 1 interferons and the th17 response in tuberculosis: lessons learned from autoimmune diseases.the classical paradigm of tuberculosis (tb) immunity, with a central protective role for th1 responses and ifn-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing th1 immunity. moreover, preclinical tb models have shown that increasing ifn-γ responses in the lungs is more damaging to the host than to the pathogen. type 1 interferon signaling and altered th17 responses have also been associated with active tb, but their functiona ...201728424682
the within-host population dynamics of mycobacterium tuberculosis vary with treatment efficacy.combination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. the mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. we address this question by studying the population dynamics of mycobacterium tuberculosis ...201728424085
erratum to: rhodococcus erythropolis as a host for expression, secretion and glycosylation of mycobacterium tuberculosis proteins. 201728424079
zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase streptomyces coelicolor glgei-v279s.we synthesized and evaluated new zwitterionic inhibitors against glycoside hydrolase-like phosphorylase streptomyces coelicolor (sco) glgei-v279s which plays a role in α-glucan biosynthesis. sco glgei-v279s serves as a model enzyme for validated anti-tuberculosis (tb) target mycobacterium tuberculosis (mtb) glge. pyrrolidine inhibitors 5 and 6 were designed based on transition state considerations and incorporate a phosphonate on the pyrrolidine moiety to expand the interaction network between t ...201728422240
accurate and effective multidrug-resistant mycobacterium tuberculosis detection method using gap-filling ligation coupled with high-resolution capillary electrophoresis-based single strand conformation polymorphism.tuberculosis (tb) has severely threatened public health via emerging multidrug-resistant (mdr) and extensively drug-resistant (xdr) mycobacterium tuberculosis (mtb) strains. for effective tb treatment, rapid, accurate, and multiplex detection of drug resistance is extremely important. however, conventional methods for tb diagnosis are time consuming and have a limited effect on treatment. nucleic acid-based molecular detection methods have been developed as an effective mdr/xdr-tb diagnosis tech ...201728422112
high detection rates of urine mycobacterium tuberculosis in patients with suspected miliary tuberculosis.objective the utility of detecting mycobacterium tuberculosis in urine samples from patients with pulmonary tuberculous with diffuse small nodular shadows (suspected miliary tuberculosis (mtb)) is still unclear in japan. a retrospective cross-sectional study was conducted to investigate the detection rates of m. tuberculosis in urine of patients with suspected mtb. methods among 687 hospitalized patients with tuberculosis, 45 with culture-confirmed suspected mtb and the data of culture and polym ...201728420836
antibacterial, antifungal and antimycobacterial compounds from cyanobacteria.infections from multidrug resistant (mdr) pathogenic bacteria, fungi and mycobacterium tuberculosis remain progressively intractable. the search of effective antimicrobials from other possible non-conventional sources against mdr pathogenic bacteria, fungi and mycobacteria is call of the day. this review considers 121 cyanobacterial compounds or cyano-compounds with antimicrobial activities. chemical structures of cyano-compounds were retrieved from chemspider and pubchem databases and were visu ...201728419973
mycobacterium tuberculosis proteasomal atpase mpa has a β-grasp domain that hinders docking with the proteasome core protease.mycobacterium tuberculosis (mtb) has a proteasome system that is essential for its ability to cause lethal infections in mice. a key component of the system is the proteasomal adenosine triphosphatase (atpase) mpa, which captures, unfolds, and translocates protein substrates into the mtb proteasome core particle for degradation. here, we report the crystal structures of near full-length hexameric mtb mpa in apo and adp-bound forms. surprisingly, the structures revealed a ubiquitin-like β-grasp d ...201728419599
activation of tlr7 inhibition of mycobacterium tuberculosis survival by autophagy in raw 264.7 macrophages.the aim of the study was to evaluate the effect of regulation of tlr7 on mycobacterium tuberculosis (mtb) survival in macrophages. tlr7 expression in macrophages infected by mtb was detected by rt-pcr and western blotting. regulation of tlr7 was achieved by single strand rna (ssrna) or sirna. the effects of tlr7 on mtb survival and cell viability were detected by acid fast staining and cell counting kit-8, respectively. cell ultrastructure was observed via transmission electron microscopy (tem), ...201728419514
mutations in streptomycin resistance genes and their relationship to streptomycin resistance and lineage of mycobacterium tuberculosis thai isolates.streptomycin (sm) is recommended by the world health organization (who) as a part of standard regimens for retreating multidrug-resistant tuberculosis (mdr-tb) cases. the incidence of mdr-tb in retreatment cases was 19% in thailand. to date, information on sm resistance (smr) gene mutations correlated to the smr of mycobacterium tuberculosis thai isolates is limited. in this study, the mutations in rpsl, rrs, gidb, and whib7 were investigated and their association to smr and the lineage of m. tu ...201728416956
efflux attenuates the antibacterial activity of q203 in mycobacterium tuberculosis.new and improved treatments for tuberculosis (tb) are urgently needed. recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available antituberculosis agents. the aim of this study was to evaluate the effectiveness of verapamil in combination with the antituberculosis drug candidate q203, which has recently been developed and is currently under clinical trials as a potentia ...201728416541
inhibition of the pi3k-akt-mtor signaling pathway in t lymphocytes in patients with active tuberculosis.to investigate pi3k-akt-mtor signaling pathway changes and the proliferation of foxp3(+)treg cells in patients with active tuberculosis.201728416440
structural analysis of the interaction between spiroisoxazoline smart-420 and the mycobacterium tuberculosis repressor ethr2.inhibition of transcriptional regulators of bacterial pathogens with the aim of reprogramming their metabolism to modify their antibiotic susceptibility constitutes a promising therapeutic strategy. one example is the bio-activation of the anti-tubercular pro-drug ethionamide, which activity could be enhanced by inhibiting the transcriptional repressor ethr. recently, we discovered that inhibition of a second transcriptional repressor, ethr2, leads to the awakening of a new ethionamide bio-activ ...201728416386
smrt genome assembly corrects reference errors, resolving the genetic basis of virulence in mycobacterium tuberculosis.the genetic basis of virulence in mycobacterium tuberculosis has been investigated through genome comparisons of virulent (h37rv) and attenuated (h37ra) sister strains. such analysis, however, relies heavily on the accuracy of the sequences. while the h37rv reference genome has had several corrections to date, that of h37ra is unmodified since its original publication.201728415976
antitubercular activity of zno nanoparticles prepared by solution combustion synthesis using lemon juice as bio-fuel.in this study, we report the synthesis, structural and morphological characteristics of zinc oxide (zno) nanoparticles using solution combustion synthesis method where lemon juice was used as the fuel. in vitro anti-tubercular activity of the synthesized zno nanoparticles and their biocompatibility studies, both in vitro and in vivo were carried out. the synthesized nanoparticles showed inhibition of mycobacterium tuberculosis h37ra strain at concentrations as low as 12.5μg/ml. in vitro cytotoxi ...201728415385
fullerene-doped polyaniline as new redox nanoprobe and catalyst in electrochemical aptasensor for ultrasensitive detection of mycobacterium tuberculosis mpt64 antigen in human serum.tuberculosis caused by mycobacterium tuberculosis (mtb) is still a major threat to global public health. however, the existing methods for mtb detection are usually complicated and time consuming with unsatisfactory sensitivity and specificity. in this work, a relatively simple and ultrasensitive electrochemical aptasensor based on novel signal generation and amplification was constructed for the determination of mtb antigen mpt64. the coil-like fullerene (c60)-doped polyaniline (c60-pan) nanohy ...201728414975
transcriptional networks are associated with resistance to mycobacterium tuberculosis infection.understanding mechanisms of resistance to m. tuberculosis (m.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases, such as hiv.201728414762
a m. avium complex spondylodiscitis in a middle-aged woman with diabetes.spondylodiscitis, the inflammation of the vertebral bodies and the intervertebral disk space, is the reason for low back pain in a minority of cases. this is caused by various pathogens. mycobacterium tuberculosis is responsible for 17-39% of all the cases of spondylodiscitis. on the contrast, spondylodiscitis from non tuberculous mycobacteria is extremely rare in literature. we describe a 68 -year old diabetic woman which is the first case of bone marrow involvement by m. intracellulare (member ...201728413773
investigation of omnigene·sputum performance in delayed tuberculosis testing by smear, culture, and xpert mtb/rif assays in uganda.omnigene·sputum (om-s) is a sample transport reagent designed to work with all tuberculosis diagnostics while eliminating the need for cold chain. om-s-treated sputum samples were assayed in several tests after multiday holds. raw sputa from 100 patients underwent direct smear microscopy, were manually split and assigned to the om-s group [om-s added at collection (no other processing required) and tested after 0- to 5-day holds at room temperature] or standard-of-care (soc) group (naoh/n-acetyl ...201728413105
digitizing medicines for remote capture of oral medication adherence using co-encapsulation.high-resolution measurement of medication adherence is essential to personalized drug therapy . an fda-cleared device, using an edible ingestion sensor (is), external wearable patch and paired mobile device, can detect and record ingestion events. oral medications must be combined with an is to generate precise 'digitized-medication' ingestion records. we developed a gmp-protocol to repackage oral medications with the is within certified capsugel® capsules, termed co-encapsulation (coe). a rando ...201728597911
pathology of tuberculosis: how the pathology of human tuberculosis informs and directs animal models.tuberculosis (tb) is a chronic inflammatory disease caused by the pathogenic bacterium mycobacterium tuberculosis. a wide variety of host- and pathogen-associated variables influence the clinical manifestation of tb in different individuals within the human population. as a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition. due to the lack of appropriate tissues from human tb patients, a variety of animal models ...201728597826
mycobacterial biofilms: revisiting tuberculosis bacilli in extracellular necrotizing lesions.under detergent-free in vitro conditions, mycobacterium tuberculosis, the etiological agent of tuberculosis in humans, spontaneously forms organized multicellular structures called biofilms. moreover, in vitro biofilms of m. tuberculosis are more persistent against antibiotics than their single-cell planktonic counterparts, thereby raising questions about the occurrence of biofilms in the host tissues and their significance in persistence during chemotherapy of tuberculosis. in this article, we ...201728597824
oxidative phosphorylation as a target space for tuberculosis: success, caution, and future directions.the emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. the mycobacterium tuberculosis complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the ab ...201728597820
killing mycobacterium tuberculosis in vitro: what model systems can teach us.tuberculosis is one of the most successful human diseases in our history due in large part to the multitude of virulence factors exhibited by the causative agent, mycobacterium tuberculosis. understanding the pathogenic nuances of this organism in the context of its human host is an ongoing topic of study facilitated by isolating cells from model organisms such as mice and non-human primates. however, m. tuberculosis is an obligate intracellular human pathogen, and disease progression and outcom ...201728597814
mycobacterium tuberculosis in the face of host-imposed nutrient limitation.coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. simply put, bacterial pathogens are just looking for food. as a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunit ...201728597811
first insight into the molecular epidemiology of mycobacterium tuberculosis isolates from the minority enclaves of southwestern china.yunnan is a province located in southwestern china. the aim of this study was to investigate the genetic diversity of mycobacterium tuberculosis (mtb) strains circulating in yunnan province. we used spoligotyping and a 12-locus high-resolution vntr set to identify a total of 271 mtb isolates collected from six prefectures' yunnan. all the 271 patients were classified as 11 different ethnic groups, including 133 han patients (49.1%) and 138 minority patients (50.9%). spoligotyping analyses reveal ...201728596961
epigenetic regulation of matrix metalloproteinase-1 and -3 expression in mycobacterium tuberculosis infection.in pulmonary tuberculosis (tb), the inflammatory immune response against mycobacterium tuberculosis (mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. matrix metalloproteinase (mmp)-1 is a host enzyme critical for the development of cavitation. mmp expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in mtb-associated induction of mmp-1 is unk ...201728596772
role of second-line injectable antituberculosis drugs in the treatment of mdr/xdr tuberculosis.second-line injectable antituberculosis drugs (aminoglycosides and capreomycin) are the main drugs used in the management of resistant tuberculosis. their preserved efficacy in the case of multi-drug-resistant bacillus is counterbalanced by frequent adverse events. adverse events are linked to the drugs themselves and to the recommended 8-month period of parenteral administration. in numerous countries facing a high incidence of multi-drug-resistant tuberculosis, treatment is administered by int ...201728595939
prevalence and risk factors for latent tuberculosis infection among healthcare workers in nampula central hospital, mozambique.healthcare workers in high tuberculosis burdened countries are occupationally exposed to the tuberculosis disease with uncomplicated and complicated tuberculosis on the increase among them. most of them acquire mycobacterium tuberculosis but do not progress to the active disease - latent tuberculosis infection. the objective of this study was to assess the prevalence and risk factors associated with latent tuberculosis infection among healthcare workers in nampula central hospital, mozambique.201728595594
synthesis of 99mtc-rifabutin: a potential tuberculosis radiodiagnostic agent.rifabutin (rfn) is bactericidal antibiotic with a very broad spectrum of activity against gram positive & gram negative organisms including pseudomonas aeruginosa and specifically mycobacterium tuberculosis.201728595542
[resection of a tuberculous abscess of the thoracic wall].the patient was a 76-year-old man. chest computed tomography revealed an abscess of the chest wall incidentally. mycobacterium tuberculosis was detected by the aspiration of the abscess. since the abscess cavity exhibited a larger trend in spite of 3 months of antituberculosis chemotherapy, surgical resection was performed. during the operation, indigo stain was injected thorough an aspiration tube to visualize the spread of the abscess. the abscess was completely resected with combined partial ...201728595221
the introduction of mesenchymal stromal cells induces different immunological responses in the lungs of healthy and m. tuberculosis infected mice.mesenchymal stromal cells (msc) have strong immunomodulatory properties and therefore can be used to control inflammation and tissue damage. it was suggested recently that msc injections can be used to treat multi-drug resistant tuberculosis (tb). however, msc trafficking and immunomodulatory effects of msc injections during mycobacterium tuberculosis (mtb) infection have not been studied. to address this issue we have analyzed msc distribution in tissues and local immunological effects of msc i ...201728594940
structure-based optimization of pyridoxal 5'-phosphate-dependent transaminase enzyme (bioa) inhibitors that target biotin biosynthesis in mycobacterium tuberculosis.the pyridoxal 5'-phosphate (plp)-dependent transaminase bioa catalyzes the second step in the biosynthesis of biotin in mycobacterium tuberculosis (mtb) and is an essential enzyme for bacterial survival and persistence in vivo. a promising bioa inhibitor 6 containing an n-aryl, n'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. here, we explore the structure-activity relationships (sar) through the design, synthesis, and biological evaluation of a syste ...201728594172
second generation multiple reaction monitoring assays for enhanced detection of ultra-low abundance mycobacterium tuberculosis peptides in human serum.mycobacterium tuberculosis (mtb) is the causative agent of tuberculosis (tb), the number one cause of death due to an infectious disease. tb diagnosis is performed by microscopy, culture or pcr amplification of bacterial dna, all of which require patient sputum or the biopsy of infected tissue. detection of mycobacterial products in serum, as biomarkers of diagnosis or disease status would provide an improvement over current methods. due to the low-abundance of mycobacterial products in serum, w ...201728592925
validation and implementation of clinical laboratory improvements act-compliant whole-genome sequencing in the public health microbiology laboratory.public health microbiology laboratories (phls) are on the cusp of unprecedented improvements in pathogen identification, antibiotic resistance detection, and outbreak investigation by using whole-genome sequencing (wgs). however, considerable challenges remain due to the lack of common standards. here, we describe the validation of wgs on the illumina platform for routine use in phls according to clinical laboratory improvements act (clia) guidelines for laboratory-developed tests (ldts). we dev ...201728592550
salt-regulated reversible fibrillation of mycobacterium tuberculosis isocitrate lyase: concurrent restoration of structure and activity.protein fibrillation is associated with a number of neurodegenerative diseases. nevertheless, several proteins not related to disease can also form fibrils in vitro under specific conditions. in the present study, we demonstrate the reversible fibrillation of a globular protein that is modulated by salt under physiological ph. mycobacterium tuberculosis isocitrate lyase (mtbicl) is a crucial enzyme involved in the glyoxylate shunt and a potential drug target against m. tuberculosis infection. un ...201728591590
detection of tuberculosis drug resistance: a comparison by mycobacterium tuberculosis mlpa assay versus genotype®mtbdrplus.to cope with the emergence of multidrug-resistant tuberculosis (mdr-tb), new molecular methods that can routinely be used to screen for a wide range of drug resistance related genetic markers in the mycobacterium tuberculosis genome are urgently needed.201728591399
epsp synthase flexibility is determinant to its function: computational molecular dynamics and metadynamics studies.flexibility is involved in a wide range of biological processes, such as protein assembly and binding recognition. epsp synthase is an enzyme that must undergo a large conformational change to accommodate its ligands into its binding cavity. however, although the structure of epsp synthase has been determined, its plasticity has not been explored in depth. therefore, in this work, we extensively examined the influence of the flexibility of mycobacterium tuberculosis epsp (mtepsp) synthase on the ...201728589464
latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents.the introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-tnf), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (tb). screening for latent tb infection (ltbi) is strongly recommended before starting therapy with anti-tnf agents. the objective of this study was to identify the prevalence of ltbi and tb among patients with rheumatic diseases on anti-tnf agents. this is a cross-sectional study. the electronic medical records o ...201728589321
a case report on complicated tuberculous meningitis.tuberculous meningitis (tbm) is associated with significant complications of central nervous system. it is accompanied by nonspecific and heterogeneous clinical symptoms. we focused on the significance of early diagnosis and prompt treatment. we describe a case of tbm in a 19-year-old asian female. she had a progressive motor weakness with no sensory findings. she was started on antituberculous therapy. her magnetic resonance imaging (mri) contrast of dorsolumbar spine showed syringomyelia. her ...201728589071
identification and evaluation of the novel immunodominant antigen rv2351c from mycobacterium tuberculosis.there is an urgent need for new immunodominant antigens to improve the diagnosis of tuberculosis (tb) and the efficacy of the tb vaccine to control the disease worldwide. in this study, we evaluated the diagnostic potential of a novel mycobacterium tuberculosis (mtb)-specific antigen, rv2351c, from region of difference (rd) 7 of the mtb genome, and investigated the potency of the vaccine by identifying its immunological function in human and animal immunological experiments. twenty t-cell epitop ...201728588287
mycobacterium tuberculosis beijing genotype family strain isolated from naturally infected plateau zokor (myospalax baileyi) in china. 201728588286
optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent mycobacterium tuberculosis.in the absence of a validated correlate of protection or robust animal models for human tuberculosis, mycobacterial growth inhibition assays (mgias) aim to assess vaccines ability to inhibit mycobacterial growth in-vitro. we optimised a reproducible murine splenocyte mgia based on in-vitro infection with virulent mycobacterium tuberculosis (m.tb) erdman. we identified splenocyte viability as a problem in state-of-art mgia protocols, which can be improved by simple changes in culture conditions ...201728588268
clinical presentation of adult pulmonary tuberculosis (ptb): a study of 103 cases from a tertiary care hospital.tuberculosis, one of the oldest diseases known to affect humans, is a major cause of death worldwide. the disease, which is caused by the bacteria mycobacterium tuberculosis complex, usually affects the lungs, although other organs are involved in up to one-third of causes. if properly treated, tuberculosis caused by drug-susceptible strains is curable in virtually all cases. if untreated, the disease may be fatal within five years in 50-65% of cases. transmission usually takes place through the ...201728588156
mycobacterium tuberculosis rv3615c is a highly immunodominant antigen and specifically induces potent th1-type immune responses in tuberculosis pleurisy.t-cell responses have been demonstrated to be essential for preventing mycobacterium tuberculosis infection. the th1-cytokines produced by t cells, such as inf-γ, il-2, and tnf-α, not only limit the invasion of m. tuberculosis but also eliminate the pathogen at the site of infection. bacillus calmette-guérin (bcg) is known to induce th1-type responses but the protection is inadequate. identification of immunogenic components, in addition to those expressed in bcg, and induction of a broad spectr ...201728588103
evaluation of a novel line probe assay to detect resistance to pyrazinamide, a key drug used for tuberculosis treatment.the development of rapid molecular diagnostic assays for pyrazinamide (pza) resistance is considered technically challenging as mutations are highly diverse, scattered along the full length of the pnca gene and not all are associated with pza resistance. we evaluated the performance of the novel genoscholar pza-tb ii line probe assay (pza-lpa2; nipro corporation, japan).201728587904
identification and synthesis of novel inhibitors of mycobacterium atp synthase.a non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against m. smegmatis atp synthase. herein, we disclose our efforts to develop the structure activity relationship against mycobacterium tuberculosis (mtb.h37rv strain) around the identified hit 1. a scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against mtb.h37rv.201728587823
advances in drug discovery of new antitubercular multidrug-resistant compounds.tuberculosis (tb), a disease caused mainly by the mycobacterium tuberculosis (mtb), is according to the world health organization (who) the infectious disease responsible for the highest number of deaths worldwide. the increased number of multidrug-resistant (mdr-tb) and extensively drug-resistant (xdr-tb) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. the scenario of drug discovery becomes alarming when it ...201728587160
tea drinking and its association with active tuberculosis incidence among middle-aged and elderly adults: the singapore chinese health study.experimental studies showed that tea polyphenols may inhibit growth of mycobacterium tuberculosis. however, no prospective epidemiologic study has investigated tea drinking and the risk of active tuberculosis. we investigated this association in the singapore chinese health study, a prospective population-based cohort of 63,257 chinese aged 45-74 years recruited between 1993 and 1998 in singapore. information on habitual drinking of tea (including black and green tea) and coffee was collected vi ...201728587081
delayed and unreported drug-susceptibility testing results in the us national tuberculosis surveillance system, 1993-2014.drug-susceptibility testing (dst) of mycobacterium tuberculosis is necessary for identifying drug-resistant tuberculosis, administering effective treatment regimens, and preventing the spread of drug-resistant tuberculosis. dst is recommended for all culture-confirmed cases of tuberculosis. we examined trends in delayed and unreported dst results in the centers for disease control and prevention's national tuberculosis surveillance system.201728586626
clinical implications of new drugs and regimens for the treatment of drug-resistant tuberculosis.the emergence of drug-resistant tuberculosis (tb) is a growing problem worldwide. the lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. therefore, new tb drugs able to bolster the current tb treatment regimen are urgently required. novel drugs that are effective and safe against mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible tb and multi-dru ...201728584788
identification of novel efflux proteins rv0191, rv3756c, rv3008, and rv1667c involved in pyrazinamide resistance in mycobacterium tuberculosis.pyrazinamide (pza) is a critical drug used for the treatment of tuberculosis (tb). pza is a prodrug that requires conversion to the active component pyrazinoic acid (poa) by pyrazinamidase (pzase) encoded by the pnca gene. although resistance to pza is mostly caused by pnca mutations and less commonly by rpsa, pand, and clpc1 mutations, clinical strains without these mutations are known to exist. while efflux of poa was demonstrated in mycobacterium tuberculosis previously, the efflux proteins i ...201728584158
t cell-derived il-10 impairs host resistance to mycobacterium tuberculosis infection.tuberculosis (tb), caused by mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. cd4(+) t cells and several cytokines, such as the th1 cytokine ifn-γ, are critical in the control of this infection. conversely, the immunosuppressive cytokine il-10 has been shown to dampen th1 cell responses to m. tuberculosis infection impairing bacterial clearance. however, the critical cellular source of il-10 during m. tuberculosis infectio ...201728584007
tuberculosis arthritis of the sternoclavicular joint after uncomplicated falciparum malaria: a case report.malaria and tuberculosis are co-endemic in many developing countries. however their associations are rarely reported. yet, it has been suggested that a pathological process may link the two diseases.201728583115
qsar-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity.new anti-tuberculosis (anti-tb) drugs are urgently needed to battle drug-resistant mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. in this work, we have continued the efforts to develop chalcone-based anti-tb compounds by using an in silico design and qsar-driven approach. initially, we developed sar rules and binary qsar models using literature data for targeted design of new heteroaryl chalcone compounds with anti-tb activity. using these models, we ...201728582669
aberrant plasma il-7 and soluble il-7 receptor levels indicate impaired t-cell response to il-7 in human tuberculosis.t-cell proliferation and generation of protective memory during chronic infections depend on interleukin-7 (il-7) availability and receptivity. regulation of il-7 receptor (il-7r) expression and signalling are key for il-7-modulated t-cell functions. aberrant expression of soluble (s) and membrane-associated (m) il-7r molecules is associated with development of autoimmunity and immune failure in acquired immune deficiency syndrome (aids) patients. here we investigated the role of il-7/il-7r on t ...201728582466
il17a augments autophagy in mycobacterium tuberculosis-infected monocytes from patients with active tuberculosis in association with the severity of the disease.during mycobacterial infection, macroautophagy/autophagy, a process modulated by cytokines, is essential for mounting successful host responses. autophagy collaborates with human immune responses against mycobacterium tuberculosis (mt) in association with specific ifng secreted against the pathogen. however, ifng alone is not sufficient to the complete bacterial eradication, and other cytokines might be required. actually, induction of th1 and th17 immune responses are required for protection ag ...201728581888
characteristics of drug resistant tuberculosis in sanatoria of north korea.although several reports about drug-resistant tuberculosis (tb) in north korea have been published, a nationwide surveillance on this disease remains to be performed. this study aims to analyze the drug resistance patterns of mycobacterium tuberculosis among the patients in the sanatoria of north korea, especially during the period when second-line drugs (slds) had not yet been officially supplied to this country. the eugene bell foundation (ebf) transferred 947 sputum specimens obtained from 66 ...201728581266
a single tube system for the detection of mycobacterium tuberculosis dna using gold nanoparticles based fret assay.the global combat against mtb is limited by challenges in accurate affordable detection. in this study, a rapid, affordable, single tube system for detection of unamplified mtb16s rdna was developed. utilizing a aunp based fret system, this assay achieved a sensitivity and specificity of 98.6% and 90% respectively.201728579440
construction of human masp-2-ccp1/2sp, ccp2sp, sp plasmid dna nanolipoplexes and the effects on tuberculosis in bcg-infected mice.the lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. the serine protease of masp-2 plays an essential role in complement activation of the lectin pathway. the c-terminal segment of masp-2 is comprised of the ccp1-ccp2-sp domains, and is the crucial catalytic segment. however, what is the effect of ccp1-ccp2-sp domains in controlling chronic infection is unknown. in order to evaluate the potential impact of ccp1-ccp2-sp domain ...201728578092
the synthesis and evaluation of triazolopyrimidines as anti-tubercular agents.we identified a di-substituted triazolopyrimidine with anti-tubercular activity against mycobacterium tuberculosis. three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. a number of compounds displayed sub-micromolar activity against mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. non-substituted aromatic rings at c5 and a two-carbon chain ...201728576632
functional details of the mycobacterium tuberculosis vapbc26 toxin-antitoxin system based on a structural study: insights into unique binding and antibiotic peptides.toxin-antitoxin (ta) systems are essential for bacterial persistence under stressful conditions. in particular, mycobacterium tuberculosis express vapbc ta genes that encode the stable vapc toxin and the labile vapb antitoxin. under normal conditions, these proteins interact to form a non-toxic ta complex, but the toxin is activated by release from the antitoxin in response to unfavorable conditions. here, we present the crystal structure of the m. tuberculosis vapbc26 complex and show that the ...201728575388
in vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant mycobacterium tuberculosis.biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-tb activity when combined with rifampicin both in vitro and in the mouse model of tb chemotherapy. we hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant mycobacterium tuberculosis .201728575382
the incremental value of repeated induced sputum and gastric aspirate samples for the diagnosis of pulmonary tuberculosis in young children with acute community-acquired pneumonia.mycobacterium tuberculosis (mtb) contributes to the pathogenesis of childhood acute community-acquired pneumonia in settings with a high tuberculosis burden. the incremental value of a repeated induced sputum (is) sample, compared with a single is or gastric aspirate (ga) sample, is not well known.201728575364
high rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine (3hp) for latent mycobacterium tuberculosis infection.rcts demonstrated the newest ltbi regimen, 12 weekly doses of directly observed isoniazid and rifapentine (3hp), as efficacious as 9 months of isoniazid (9h) with a greater completion rate (82% versus 69%); however, 3hp has not been assessed in routine health care settings.201728575208
genetic diversity & drug sensitivity profiles of mycobacterium tuberculosis isolates from two slums of jaipur city, rajasthan, india.slums are considered as hotspots of tuberculosis (tb). the study of genetic diversity and drug susceptibility profile of mycobacterium tuberculosis (mtb) will help understand the transmission dynamics and can be used for better prevention and control of the disease. the aim of this study was to determine the drug susceptibility profiles and genetic diversity using the random amplified polymorphic dna (rapd) and mycobacterial interspersed repetitive units-variable number of tandem repeats (miru v ...201728574018
line probe assay for detection of mycobacterium tuberculosis complex: an experience from central india.mycobacterium tuberculosis complex may sometimes not be detected in sputum samples of suspected multidrug-resistant tuberculosis (mdr-tb) patients by line probe assay (lpa) even though they are smear positive for acid-fast bacilli (afb). this retrospective analysis was attempted to understand and document our experience with lpa for detection of m. tuberculosis complex and diagnosis of mdr-tb under programmatic conditions.201728574017
the ser/thr protein kinase protein-protein interaction map of m. tuberculosis.mycobacterium tuberculosis (mtb) is the causative agent of tuberculosis, the leading cause of death among all infectious diseases. there are 11 eukaryotic-like serine/threonine protein kinases (stpks) in mtb, which are thought to play pivotal roles in cell growth, signal transduction and pathogenesis. however, their underlying mechanisms of action remain largely uncharacterized. in this study, using a mtb proteome microarray, we have globally identified the binding proteins in mtb for all of the ...201728572091
individual- and neighborhood-level contextual factors are associated with mycobacterium tuberculosis transmission: genotypic clustering of cases in michigan, 2004-2012.using genotyping data of mycobacterium tuberculosis isolates from new cases reported to the tuberculosis (tb) surveillance program, we evaluated risk factors for recent tb transmission at both the individual- and neighborhood- levels among u.s.-born and foreign-born populations.201728571914
bioinformatics approach to prioritize known drugs towards repurposing for tuberculosis.new drugs are urgently needed to cure tuberculosis (tb) in a short period of time without causing any adverse effects since currently used drugs for the treatment of multi drug-resistant tb cause several adverse effects with poor success rate. therefore, we aimed to prioritize known drugs towards repurposing for tb by employing bioinformatics approach in the present study. a total of 1554 fda approved drugs were obtained from drugbank. serine/threonine-protein kinase, pknb (rv0014c) of mycobacte ...201728571806
determination and validation of a lower cut off value of cerebrospinal fluid adenosine deaminase (csf-ada) activity in diagnosis of tuberculous meningitis.tuberculous meningitis is an infection of the meninges caused by mycobacterium tuberculosis. it is one of the most common infectious diseases of the central nervous system (cns) and a major health problem in developing countries like india. if there is delay in diagnosis and initiation of specific treatment, it causes significant morbidity and mortality. csf-ada 10 u/l is the standard cut off value that is used for differentiation between tuberculous (tbm) and non-tuberculous meningitis (non-tbm ...201728571185
comparative diagnostic utility of is6110 pcr assay in csf and peripheral blood samples of tuberculous meningitis patients: a pilot study from central india.tuberculous meningitis (tbm) is the most severe form of central nervous system tuberculosis (cns-tb) and constitutes about 6% of all extrapulmonary tb (eptb) cases. most guidelines for the diagnosis and management of tbm agree on the use of simple cerebrospinal fluid (csf) analysis using molecular tools like polymerase chain reaction (pcr). however, the sensitivity of pcr varies while using a csf sample. in the present study, we have compared the diagnostic utility of pcr assay in both periphera ...201728571129
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