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pediatric pulmonary tuberculoma with a solid pulmonary nodule detected on chest computed tomography.a 14-year-old girl underwent a medical checkup for mycobacterium tuberculosis infection because her grandmother had been diagnosed with pulmonary tuberculosis three months earlier. the interferon-gamma release assay (igra) showed a positive result. the patient's chest x-ray findings were normal. chest computed tomography (ct) showed a single mass lesion in the right lower lobe of the lung. a sputum smear of acid-fast bacilli was positive; however, the polymerase chain reaction results for tuberc ...201424739618
a systematic follow-up of mycobacterium tuberculosis drug-resistance and associated genotypic lineages in the french departments of the americas over a seventeen-year period.the population of the french departments of the americas (fda) is highly influenced by the intense migratory flows with mainland france and surrounding countries of the caribbean and latin america, some of which have high incidence rates of tuberculosis (haiti: 230/100,000; guyana: 111/100,000; and suriname: 145/100,000) and drug resistance. since the development of drug resistance to conventional antituberculous drugs has a major impact on the treatment success of tuberculosis, we therefore dec ...201424738068
tuberculin skin tests versus interferon-gamma release assays in tuberculosis screening among immigrant visa applicants.objective. use of tuberculin skin tests (tsts) and interferon gamma release assays (igras) as part of tuberculosis (tb) screening among immigrants from high tb-burden countries has not been fully evaluated. methods. prevalence of mycobacterium tuberculosis infection (mtbi) based on tst, or the quantiferon-tb gold test (qft-g), was determined among immigrant applicants in vietnam bound for the united states (us); factors associated with test results and discordance were assessed; predictive value ...201424738031
crystal structure of the transcriptional regulator rv0678 of mycobacterium tuberculosis.recent work demonstrates that the mmpl (mycobacterial membrane protein large) transporters are dedicated to the export of mycobacterial lipids for cell wall biosynthesis. an mmpl transporter frequently works with an accessory protein, belonging to the mmps (mycobacterial membrane protein small) family, to transport these key virulence factors. one such efflux system in mycobacterium tuberculosis is the mmps5-mmpl5 transporter. the expression of mmps5-mmpl5 is controlled by the marr-like transcri ...201424737322
a trisubstituted benzimidazole cell division inhibitor with efficacy against mycobacterium tuberculosis.trisubstituted benzimidazoles have demonstrated potency against gram-positive and gram-negative bacterial pathogens. previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against m. tuberculosis h37rv and clinical isolates, and were not toxic to vero cells. a new series of 2-cyclohexyl-5-acylamino-6-n, n-dimethylaminobenzimidazoles derivatives has been developed based on sar studies. screen ...201424736743
synthesis, crystal studies, anti-tuberculosis and cytotoxic studies of 1-[(2e)-3-phenylprop-2-enoyl]-1h-benzimidazole derivatives.series of 1-[(2e)-3-phenylprop-2-enoyl]-1h-benzimidazole derivatives were synthesized and characterized by spectral methods. among 21 derivatives, single crystals of 3a and 3l were grown and their structural parameters were evaluated. newly synthesized compounds were screened for anti-tubercular activity and the mic was determined against mycobacterium tuberculosis h37rv by microplate alamar blue assay (maba) method. majority of the compounds exhibited a promising inhibition of m. tuberculosis a ...201424735645
optimisation of the microplate resazurin assay for screening and bioassay-guided fractionation of phytochemical extracts against mycobacterium tuberculosis.because of increased resistance to current drugs, there is an urgent need to discover new anti-mycobacterial compounds for the development of novel anti-tuberculosis drugs. the microplate resazurin assay (mra) is commonly used to evaluate natural products and synthetic compounds for anti-mycobacterial activity. however, the assay can be problematic and unreliable when screening methanolic phytochemical extracts.201524733665
prevalence and molecular characteristics of drug-resistant mycobacterium tuberculosis in hunan, china.to determine the prevalence and molecular characteristics of drug-resistant tuberculosis in hunan province, drug susceptibility testing and spoligotyping methods were performed among 171 m. tuberculosis isolates. in addition, the mutated characteristics of 12 loci, including katg, inha, rpob, rpsl, nucleotides 388 to 1084 of the rrs gene [rrs(388-1084)], embb, pnca, tlya, eis, nucleotides 1158 to 1674 of the rrs gene [rrs(1158-1674)], gyra, and gyrb, among drug-resistant isolates were also analy ...201424733464
atypical ompr/phob subfamily response regulator glnr of actinomycetes functions as a homodimer, stabilized by the unphosphorylated conserved asp-focused charge interactions.the ompr/phob subfamily protein glnr of actinomycetes is an orphan response regulator that globally coordinates the expression of genes related to nitrogen metabolism. biochemical and genetic analyses reveal that the functional glnr from amycolatopsis mediterranei is unphosphorylated at the potential phosphorylation asp(50) residue in the n-terminal receiver domain. the crystal structure of this receiver domain demonstrates that it forms a homodimer through the α4-β5-α5 dimer interface highly si ...201424733389
comparison between rflp and miru-vntr genotyping of mycobacterium tuberculosis strains isolated in stockholm 2009 to 2011.our aim was to analyze the difference between methods for genotyping of mycobacterium tuberculosis complex isolates. we collected genotyping results from restriction fragment length polymorphism (rflp) and mycobacterial interspersed repetitive units-variable numbers of tandem repeat (miru-vntr) in a geographically limited area (stockholm) during a period of three years. the number and proportion of isolates belonging to clusters was reduced by 45 and 35% respectively when combining the two metho ...201424733167
reduced virulence of an extensively drug-resistant outbreak strain of mycobacterium tuberculosis in a murine model.bacterial drug resistance is often associated with a fitness cost. large outbreaks of multidrug-resistant (mdr) and extensively drug-resistant (xdr) tb have been described that predominately affect persons with hiv infection. we obtained four closely-related mycobacterium tuberculosis strains (genotype f15/lam4/kzn) from an outbreak in kwazulu-natal (kzn), south africa, including drug-sensitive, mdr, and xdr clinical isolates. we compared the virulence of these strains in a murine model of aeros ...201424733050
mycobactericidal activity of sutezolid (pnu-100480) in sputum (eba) and blood (wba) of patients with pulmonary tuberculosis.sutezolid (pnu-100480) is a linezolid analog with superior bactericidal activity against mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. like linezolid, it is unaffected by mutations conferring resistance to standard tb drugs. this study of sutezolid is its first in tuberculosis patients.201424732289
structural and functional significance of the highly-conserved residues in mycobacterium tuberculosis acetohydroxyacid synthase.mycobacterium tuberculosis ahas is a potential target for the development of novel anti-tuberculosis agents. silico analysis showed that conserved his84 and gln86 residues lie in the catalytic dimer interface of m. tuberculosis ahas. mutational analyses of these invariants led to significant reduction in their activity with reduced affinity toward the substrate. importantly, mutation of gln86 to trp abolished complete activity. further, molecular dynamics simulation studies suggested that these ...201424731825
mubii-tb-db: a database of mutations associated with antibiotic resistance in mycobacterium tuberculosis.tuberculosis is an infectious bacterial disease caused by mycobacterium tuberculosis. it remains a major health threat, killing over one million people every year worldwide. an early antibiotic therapy is the basis of the treatment, and the emergence and spread of multidrug and extensively drug-resistant mutant strains raise significant challenges. as these bacteria grow very slowly, drug resistance mutations are currently detected using molecular biology techniques. resistance mutations are ide ...201424731071
extensively drug-resistant tuberculosis: epidemiology and management.the advent of antibiotics for the treatment of tuberculosis (tb) represented a major breakthrough in the fight against the disease. however, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. the incorrect use of anti-tb drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of mycobacterium tuberculosis strains with an expanding spectrum of resistance. the spread of multidrug ...201424729727
xpert mtb/rif assay shortens airborne isolation for hospitalized patients with presumptive tuberculosis in the united states.in the united states, individuals with presumptive pulmonary tuberculosis are placed in airborne infection isolation (aii) and assessed by smear microscopy on 3 respiratory specimens collected 8-24 hours apart. xpert mtb/rif assay (xpert) on 1, 2, or 3 specimens may be more efficient for determining aii discontinuation.201424729506
improving outcomes for multidrug-resistant tuberculosis: aggressive regimens prevent treatment failure and death.evidence is sparse regarding the optimal construction of regimens to treat multidrug-resistant (mdr) tuberculosis disease due to strains of mycobacterium tuberculosis resistant to at least both isoniazid and rifampin. given the low potency of many second-line antituberculous drugs, we hypothesized that an aggressive regimen of at least 5 likely effective drugs during the intensive phase, including a fluoroquinolone and a parenteral agent, would be associated with a reduced risk of death or treat ...201424729493
time-to-detection in culture predicts risk of mycobacterium tuberculosis transmission: a cohort study.contact screening is an essential component of all tuberculosis control strategies. we hypothesize that time-to-detection (ttd) in liquid culture of spontaneously produced sputum samples may help identify index cases at high risk of transmission.201424729491
genetic diversity of tlr2, tlr4, and vdr loci and pulmonary tuberculosis in moroccan patients.toll-like receptors (tlrs) 2, 4, and the vitamin d receptor (vdr) are central components of the innate and adaptive immunity against mycobacterium tuberculosis (mtb). tlr2, tlr4, and vdr polymorphisms were previously associated with tuberculosis (tb) and were here investigated as candidates for pulmonary tb (ptb) susceptibility in a moroccan population group.201424727508
recombinant bcg coexpressing ag85b, esat-6 and rv3620c elicits specific th1 immune responses in c57bl/6 mice.tuberculosis (tb) remains to be an enormous global health problem. the inconsistent protection efficacy of bacille calmette-guérin (bcg) calls for new vaccines for tb. one choice to improve the efficacy of bcg vaccine is recombinant bcg (rbcg). experimental evidences have revealed that ag85b, esat-6 and rv3620c are important immunodominant antigens of mycobacterium tuberculosis. in this study, we have constructed a novel rbcg expressing fusion protein ag85b-esat6-rv3620c and evaluated the immuno ...201424726737
pyrosequencing for rapid detection of tuberculosis resistance in clinical isolates and sputum samples from re-treatment pulmonary tuberculosis patients.multidrug-resistant tuberculosis (mdr-tb) is a major public health problem. early diagnosis of mdr-tb patients is essential for minimizing the risk of mycobacterium tuberculosis (mtb) transmission. the conventional drug susceptibility testing (dst) methods for detection of drug-resistant m. tuberculosis are laborious and cannot provide the rapid detection for clinical practice.201424725975
characterization of the interaction between a sirr family transcriptional factor of mycobacterium tuberculosis, encoded by rv2788, and a pair of toxin-antitoxin proteins relj/k, encoded by rv3357 and rv3358.toxin-antitoxin (ta) systems play significant roles in the regulation of bacterial growth and persistence, and their functions usually depend on protein-protein interaction between their constituent ta proteins. however, the regulatory mechanisms of these systems, particularly their interaction with other cellular components, are still poorly understood. this study investigated cross-talk between the ta module relj/k (rv3357/rv3358) and the transcriptional regulator staphylococcal iron regulator ...201424725376
suitability of is6110-rflp and miru-vntr for differentiating spoligotyped drug-resistant mycobacterium tuberculosis clinical isolates from sichuan in china.genotypes of mycobacterium tuberculosis complex (mtbc) vary with the geographic origin of the patients and can affect tuberculosis (tb) transmission. this study was aimed to further differentiate spoligotype-defined clusters of drug-resistant mtbc clinical isolates split in beijing (n = 190) versus non-beijing isolates (n = 84) from sichuan region, the second high-burden province in china, by is6110-restriction fragment length polymorphism (rflp) and 24-locus miru-vntrs. among 274 spoligotyped i ...201424724099
active site conformational changes upon reaction intermediate biotinyl-5'-amp binding in biotin protein ligase from mycobacterium tuberculosis.protein biotinylation, a rare form of post-translational modification, is found in enzymes required for lipid biosynthesis. in mycobacteria, this process is essential for the formation of their complex and distinct cell wall and has become a focal point of drug discovery approaches. the enzyme responsible for this process, biotin protein ligase, substantially varies in different species in terms of overall structural organization, regulation of function and substrate specificity. to advance the ...201424723382
replication of mycobacterium tuberculosis in retinal pigment epithelium.mycobacterium tuberculosis is an important cause of posterior uveitis in tuberculosis-endemic regions. clinical and histopathologic evidence suggests that retinal pigment epithelium (rpe) can harbor m tuberculosis. however, the mechanism of m tuberculosis phagocytosis and its growth in rpe is not clear.201424723139
differential regulation of the two-component regulatory system senx3-regx3 in mycobacterium tuberculosis.the highly successful pathogen mycobacterium tuberculosis (mtb) has evolved strategies to adapt to various stress conditions, thus promoting survival within the infected host. the two-component regulatory system (2crs) senx3-regx3, which has been implicated in the mtb response to inorganic phosphate depletion, is believed to behave as an auto-regulatory bicistronic operon. unlike other 2crs, mtb senx3-regx3 features an intergenic region (ir) containing several mycobacterium interspersed repetiti ...201424722908
suramin is a potent and selective inhibitor of mycobacterium tuberculosis reca protein and the sos response: reca as a potential target for antibacterial drug discovery.in eubacteria, reca is essential for recombinational dna repair and for stalled replication forks to resume dna synthesis. recent work has implicated a role for reca in the development of antibiotic resistance in pathogenic bacteria. consequently, our goal is to identify and characterize small-molecule inhibitors that target reca both in vitro and in vivo.201424722837
synthesis and biological evaluation of novel 2-methoxypyridylamino-substituted riminophenazine derivatives as antituberculosis agents.clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant mycobacterium tuberculosis (m. tuberculosis). however, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. with the goal of maintaining potent antituberculosis activity while improving physicochemical properties and lowering skin pigmentation potential, a series of novel riminophenazine derivat ...201424722591
the influence of sex steroid hormones in the immunopathology of experimental pulmonary tuberculosis.the relation between men and women suffering pulmonary tuberculosis is 7/3 in favor to males. sex hormones could be a significant factor for this difference, considering that testosterone impairs macrophage activation and pro-inflammatory cytokines production, while estrogens are proinflammatory mediator's inducer. the aim of this work was to compare the evolution of tuberculosis in male and female mice using a model of progressive disease. balb/c mice, male and female were randomized into two g ...201424722144
facile synthesis of benzonitrile/nicotinonitrile based s-triazines as new potential antimycobacterial agents.a common strategy to synthesize 4/6-(4-(4-methylpiperazin-1-yl)-6-(4-(4-oxo-2-phenylthiazolidin-3-yl)phenyl)-1,3,5-triazin-2-yloxy)benzonitriles/nicotinonitriles was developed by applying an efficient palladium-catalyzed c-c suzuki coupling. moreover, the synthesized compounds were also tested for their in vitro antimycobacterial activity against mycobacterium tuberculosis h37rv using bactec mgit and lowenstein-jensen mic methods. several compounds displayed profound antimycobacterial activity i ...201424721315
molecular epidemiology and genotyping of mycobacterium tuberculosis isolated in baghdad.tuberculosis (tb) remains a major health problem in iraq but the strains responsible for the epidemic have been poorly characterized. our aim was to characterize the tb strains circulating in bagdad (iraq). a total of 270 mycobacterium tuberculosis complex (mtbc) strains isolated between 2010 and 2011 from tb patients attending the center of chest and respiratory diseases in baghdad were analyzed by spoligotyping. the analysis indicated that 94.1% of the isolates belong to known genotype clades: ...201424719873
mycobacterium tuberculosis h37rv: in silico drug targets identification by metabolic pathways analysis.mycobacterium tuberculosis (mtb) is a pathogenic bacteria species in the genus mycobacterium and the causative agent of most cases of tuberculosis. tuberculosis (tb) is the leading cause of death in the world from a bacterial infectious disease. this antibiotic resistance strain lead to development of the new antibiotics or drug molecules which can kill or suppress the growth of mycobacterium tuberculosis. we have performed an in silico comparative analysis of metabolic pathways of the host homo ...201424719775
simplified microarray system for simultaneously detecting rifampin, isoniazid, ethambutol, and streptomycin resistance markers in mycobacterium tuberculosis.we developed a simplified microarray test for detecting and identifying mutations in rpob, katg, inha, embb, and rpsl and compared the analytical performance of the test to that of phenotypic drug susceptibility testing (dst). the analytical sensitivity was estimated to be at least 110 genome copies per amplification reaction. the microarray test correctly detected 95.2% of mutations for which there was a sequence-specific probe on the microarray and 100% of 96 wild-type sequences. in a blinded ...201424719444
development of a quantitative sandwich enzyme-linked immunosorbent assay for detecting the mpt64 antigen of mycobacterium tuberculosis.tuberculosis (tb) is a major infectious disease and is responsible for two million deaths annually. for the identification and quantitation of mycobacterium tuberculosis (m. tuberculosis), a causative agent of tb, a sandwich enzyme-linked immunosorbent assay (elisa) against the mpt64 protein of m. tuberculosis, an antigen marker of the m. tuberculosis complex, was developed.201424719143
progress in tuberculosis vaccine development and host-directed therapies--a state of the art review.tuberculosis continues to kill 1·4 million people annually. during the past 5 years, an alarming increase in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has been noted, particularly in eastern europe, asia, and southern africa. treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. although substantial progress in drug development for tuberculosis has been made, scientific progress towards develo ...201424717627
assessment of mycobacterium tuberculosis transmission in oxfordshire, uk, 2007-12, with whole pathogen genome sequences: an observational study.patients born outside the uk have contributed to a 20% rise in the uk's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years.201424717625
whole-genome sequencing of mycobacterium tuberculosis as an epidemiological marker. 201424717616
optimization of the microscopic observation drug susceptibility assay for four first-line drugs using mycobacterium tuberculosis reference strains and clinical isolates.the aim of this study is to determine the appropriate cut-off value and turnaround time of the microscopic observation drug susceptibility assay (mods) for isoniazid (inh), rifampicin (rmp), streptomycin (str), and ethambutol (emb).201424717372
inflammation and tuberculosis: host-directed therapies.tuberculosis (tb) is an airborne infectious disease that kills almost two million individuals every year. multidrug-resistant (mdr) tb is caused by strains of mycobacterium tuberculosis (m. tb) resistant to isoniazid and rifampin, the backbone of first-line antitubercular treatment. mdr tb affects an estimated 500,000 new patients annually. genetic analysis of drug-resistant mdr-tb showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. the ...201524717092
[lessons learned from tuberculosis outbreak cases].most tb outbreaks were caused by exposure of many people to tuberculosis bacilli due to delayed detection of initial cases who had long-lasting severe coughs and excretion of massive tuberculosis bacilli. they were also affected by several other factors, such as socio-environmental factors of the initial case; time and place of infection; and host factors of the infected persons such as immune status, infectivity, and/or pathogenicity of the bacilli. in this symposium, we learned the seriousness ...201424716362
fatal disseminated tuberculous peritonitis following spontaneous abortion: a case report.we describe a rare case of fatal disseminated tuberculous peritonitis in a young woman with rapid progressive clinical course following spontaneous abortion of 20-week gestation. clinical and laboratory findings were initially unremarkable. she underwent diagnostic laparoscopy which revealed numerous tiny implants on the peritoneum and viscera. histopathology showed chronic caseating granulomas, and the tissue culture grew mycobacterium tuberculosis. at fifth day of the antituberculous treatment ...201424716027
peritoneal tuberculosis mimicking peritoneal carcinomatosis.a 67-year-old male presented with fatigue, abdominal pain , and 30-pound weight loss over 3 months. computerized tomography (ct) abdomen displayed ascites with thickening and enhancement of the peritoneum and mottled nodular appearing as soft tissue consistent with omental caking worrisome for peritoneal carcinomatosis. a paracentesis revealed white blood cell count of 2,500 with 98% lymphocytes and serum ascites albumin gradient of 0.9 g/l. no acid-fast bacilli were seen by microscopic exam and ...201424715911
definition of cd4 immunosignatures associated with mtb.we have recently described the first true genome-wide screen for cd4(+) t-cell reactivity directed against mycobacterium tuberculosis (mtb) in latent tb-infected individuals. the approach relied on predictions of hla-binding capacity for a panel of dr, dp, and dq alleles representative of those most commonly expressed in the general population, coupled with high throughput elispot assays. the results identified hundreds of novel epitopes and antigens, and documented the novel observation that t ...201424715893
function and potentials of m. tuberculosis epitopes.study of the function of epitopes of mycobacterium tuberculosis antigens contributed significantly toward better understanding of the immunopathogenesis and to efforts for improving infection and disease control. characterization of genetically permissively presented immunodominant epitopes has implications for the evolution of the host-parasite relationship, development of immunodiagnostic tests, and subunit prophylactic vaccines. knowledge of the determinants of cross-sensitization, relevant t ...201424715888
preventing and controlling zoonotic tuberculosis: a one health approach.the expression one health refers to the unified human and veterinary approach to zoonoses, an approach that used to be identified with medicine throughout the 20th century. zoonotic tuberculosis (tb), a disease due to bacteria of the mycobacterium tuberculosis complex, is a recognized global public veterinary health problem. the significance of the health and economic threats posed by zoonotic tb has been recognized by several global health agencies, which have called for control and eradication ...201424715597
activity of 4,5-dihydro-1h-pyrazoles against mycobacterium tuberculosis and nontuberculous mycobacteria. 201424713182
tuberculosis, pulmonary cavitation, and matrix metalloproteinases.tuberculosis (tb), a chronic infectious disease of global importance, is facing the emergence of drug-resistant strains with few new drugs to treat the infection. pulmonary cavitation, the hallmark of established disease, is associated with very high bacillary burden. cavitation may lead to delayed sputum culture conversion, emergence of drug resistance, and transmission of the infection. the host immunological reaction to mycobacterium tuberculosis is implicated in driving the development of tb ...201424713029
alternative substrates reveal catalytic cycle and key binding events in the reaction catalysed by anthranilate phosphoribosyltransferase from mycobacterium tuberculosis.anprt (anthranilate phosphoribosyltransferase), required for the biosynthesis of tryptophan, is essential for the virulence of mycobacterium tuberculosis (mtb). anprt catalyses the mg2+-dependent transfer of a phosphoribosyl group from prpp (5'-phosphoribosyl-1'-pyrophosphate) to anthranilate to form pra (5'-phosphoribosyl anthranilate). mtb-anprt was shown to catalyse a sequential reaction and significant substrate inhibition by anthranilate was observed. antimycobacterial fluoroanthranilates a ...201424712732
small molecule-directed immunotherapy against recurrent infection by mycobacterium tuberculosis.tuberculosis remains the biggest infectious threat to humanity with one-third of the population infected and 1.4 million deaths and 8.7 million new cases annually. current tuberculosis therapy is lengthy and consists of multiple antimicrobials, which causes poor compliance and high treatment dropout, resulting in the development of drug-resistant variants of tuberculosis. therefore, alternate methods to treat tuberculosis are urgently needed. mycobacterium tuberculosis evades host immune respons ...201424711459
a missed tuberculosis diagnosis resulting in hospital transmission.to find the source of tuberculin skin test conversions among 38 hospital employees on 1 floor during routine testing january-february 2010.201424709722
determination of the activity of standard anti-tuberculosis drugs against intramacrophage mycobacterium tuberculosis, in vitro: mgit 960 as a viable alternative for bactec 460.bactec 460 has now been phased out, so the search for an alternative is imperative. we have determined the activity of standard anti-tuberculosis drugs against intramacrophage mycobacterium tuberculosis, in vitro, by using bactec 460 and mgit 960 methods. the minimum inhibitory concentrations of isoniazid, rifampicin, ethambutol and streptomycin against intracellular m. tuberculosis h37rv were found to be 0.2, 0.8, 8.0, and 5.0 μg/ml, respectively, by both methods. these results show a significa ...201424709416
sulfur mobilization for fe-s cluster assembly by the essential suf pathway in the plasmodium falciparum apicoplast and its inhibition.the plastid of the malaria parasite, the apicoplast, is essential for parasite survival. it houses several pathways of bacterial origin that are considered attractive sites for drug intervention. among these is the sulfur mobilization (suf) pathway of fe-s cluster biogenesis. although the suf pathway is essential for apicoplast maintenance and parasite survival, there has been limited biochemical investigation of its components and inhibitors of plasmodium sufs have not been identified. we repor ...201424709262
intracellular activity of tedizolid phosphate and ach-702 versus mycobacterium tuberculosis infected macrophages.due to the emergency of multidrug-resistant strains of mycobacterium tuberculosis, is necessary the evaluation of new compounds.201424708819
ability of preventive therapy to cure latent mycobacterium tuberculosis infection in hiv-infected individuals in high-burden settings.trials of isoniazid preventive therapy (ipt) for people living with hiv in southern africa have shown high rates of tuberculosis disease immediately after cessation of therapy. this could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent mycobacterium tuberculosis infection in hiv-infected individuals in high-tuberculosis-burden settings. we ...201424706842
propionate represses the dnaa gene via the methylcitrate pathway-regulating transcription factor, prpr, in mycobacterium tuberculosis.during infection of macrophages, mycobacterium tuberculosis, the pathogen that causes tuberculosis, utilizes fatty acids as a major carbon source. however, little is known about the coordination of the central carbon metabolism of m. tuberculosis with its chromosomal replication, particularly during infection. a recently characterized transcription factor called prpr is known to directly regulate the genes involved in fatty acid catabolism by m. tuberculosis. here, we report for the first time t ...201424705740
non-tuberculous mycobacteria and the performance of interferon gamma release assays in denmark.the quantiferon-tb-gold test (qft) is more specific than the mantoux skin-test to discriminate between mycobacterium tuberculosis (mtb) and non-tuberculous mycobacterial (ntm) infections. here we study the performance of the qft in patients with ntm disease.201424705675
the mycobacterium tuberculosis rv2745c plays an important role in responding to redox stress.tuberculosis (tb), caused by mycobacterium tuberculosis (mtb), is the leading cause of death from an infectious disease worldwide. over the course of its life cycle in vivo, mtb is exposed to a plethora of environmental stress conditions. temporal regulation of genes involved in sensing and responding to such conditions is therefore crucial for mtb to establish an infection. the rv2745c (clgr) gene encodes a clp protease gene regulator that is induced in response to a variety of stress condition ...201424705585
molecular basis of thermal stability in truncated (2/2) hemoglobins.understanding the molecular mechanism through which proteins are functional at extreme high and low temperatures is one of the key issues in structural biology. to investigate this phenomenon, we have focused on two instructive truncated hemoglobins from thermobifida fusca (tf-trhbo) and mycobacterium tuberculosis (mt-trhbo); although the two proteins are structurally nearly identical, only the former is stable at high temperatures.201424704259
optimal control of a two-strain tuberculosis-hiv/aids co-infection model.tuberculosis is a bacterial disease caused by mycobacterium tuberculosis (tb). the risk for tb infection greatly increases with hiv infection; tb disease occurs in 7-10% of patients with hiv infection each year, increasing the potential for transmission of drug-resistant mycobacterium tuberculosis strains. in this paper a deterministic model is presented and studied for the transmission of tb-hiv/aids co-infection. optimal control theory is then applied to investigate optimal strategies for cont ...201424704209
the intracellular b30.2 domain of butyrophilin 3a1 binds phosphoantigens to mediate activation of human vγ9vδ2 t cells.in humans, vγ9vδ2 t cells detect tumor cells and microbial infections, including mycobacterium tuberculosis, through recognition of small pyrophosphate containing organic molecules known as phosphoantigens (pags). key to pag-mediated activation of vγ9vδ2 t cells is the butyrophilin 3a1 (btn3a1) protein that contains an intracellular b30.2 domain critical to pag reactivity. here, we have demonstrated through structural, biophysical, and functional approaches that the intracellular b30.2 domain of ...201424703779
the bcg replacement vaccine vpm1002: from drawing board to clinical trial.tuberculosis remains a major health threat and vaccines better than bacillus calmette-guérin (bcg) are urgently required. here we describe our experience with a recombinant bcg expressing listeriolysin and deficient in urease. this potential replacement vaccine has demonstrated superior efficacy and safety over bcg in mycobacterium tuberculosis aerosol-challenged mice and was safe in numerous animal models including immune-deficient mice, guinea pigs, rabbits and nonhuman primates. phase i clini ...201424702486
evaluation of als assay of tb-sa for diagnosis of pulmonary tuberculosis.the study evaluated tuberculosis specific antigen (tb-sa) antibody in lymphocyte supernatant (als) assay for diagnosis of pulmonary tuberculosis (ptb). the mean concentration of tb-sa als in ptb patients was significantly higher than that of two control groups (non-ptb patients and healthy subjects, p < 0.001). the area under the curve of the als assay were 0.960 (0.904-0.988, ptb vs healthy subjects), and were 0.822 (0.739-0.887, ptb vs non-ptb patients), respectively. our data indicated the al ...201524702118
immunomagnetic isolation of pathogen-containing phagosomes and apoptotic blebs from primary phagocytes.macrophages and polymorphonuclear neutrophils are professional phagocytes essential in the initial host response against intracellular pathogens such as mycobacterium tuberculosis. phagocytosis is the first step in phagocyte-pathogen interaction, where the pathogen is engulfed into a membrane-enclosed compartment termed a phagosome. subsequent effector functions of phagocytes result in killing and degradation of the pathogen by promoting phagosome maturation, and, terminally, phago-lysosome fusi ...201424700322
comparison of four different crystal forms of the mycobacterium tuberculosis esx-1 secreted protein regulator espr.the mycobacterium tuberculosis esx-1 secreted protein regulator (espr, rv3849) is the key protein that delivers bacterial proteins into the host cell during mycobacterial infection. espr binds directly to the espacd operon and is involved in transcriptional activation. in the current study, m. tuberculosis espr has been crystallized and its x-ray structure has been determined at 3.3 å resolution in a p3221 crystal form. espr forms a physiological dimer in the crystal. each espr monomer contains ...201424699733
1.55 å resolution x-ray crystal structure of rv3902c from mycobacterium tuberculosis.the crystallographic structure of the mycobacterium tuberculosis (tb) protein rv3902c (176 residues; molecular mass of 19.8 kda) was determined at 1.55 å resolution. the function of rv3902c is unknown, although several tb genes involved in bacterial pathogenesis are expressed from the operon containing the rv3902c gene. the unique structural fold of rv3902c contains two domains, each consisting of antiparallel β-sheets and α-helices, creating a hand-like binding motif with a small binding pocket ...201424699730
structural basis for the redox sensitivity of the mycobacterium tuberculosis sigk-rska σ-anti-σ complex.the host-pathogen interactions in mycobacterium tuberculosis infection are significantly influenced by redox stimuli and alterations in the levels of secreted antigens. the extracytoplasmic function (ecf) σ factor σ(k) governs the transcription of the serodominant antigens mpt70 and mpt83. the cellular levels of σ(k) are regulated by the membrane-associated anti-σ(k) (rska) that localizes σ(k) in an inactive complex. the crystal structure of m. tuberculosis σ(k) in complex with the cytosolic dom ...201424699647
characterization of the proline-utilization pathway in mycobacterium tuberculosis through structural and functional studies.the proline-utilization pathway in mycobacterium tuberculosis (mtb) has recently been identified as an important factor in mtb persistence in vivo, suggesting that this pathway could be a valuable therapeutic target against tuberculosis (tb). in mtb, two distinct enzymes perform the conversion of proline into glutamate: the first step is the oxidation of proline into δ(1)-pyrroline-5-carboxylic acid (p5c) by the flavoenzyme proline dehydrogenase (prub), and the second reaction involves convertin ...201424699642
a random sequential mechanism of aminoglycoside acetylation by mycobacterium tuberculosis eis protein.an important cause of bacterial resistance to aminoglycoside antibiotics is the enzymatic acetylation of their amino groups by acetyltransferases, which abolishes their binding to and inhibition of the bacterial ribosome. enhanced intracellular survival (eis) protein from mycobacterium tuberculosis (mt) is one of such acetyltransferases, whose upregulation was recently established as a cause of resistance to aminoglycosides in clinical cases of drug-resistant tuberculosis. the mechanism of amino ...201424699000
what is the most reliable solid culture medium for tuberculosis treatment trials?we conducted a prospective study to determine which solid medium is the most reliable overall and after two months of therapy to detect mycobacterium tuberculosis complex (mtb). mtb isolation and contamination rates on lj and middlebrook 7h10 and 7h11 agar with and without selective antibiotics were examined in a single laboratory and compared against a constructed reference standard and mgit 960 results. of 50 smear positive adults with pulmonary tb enrolled, 45 successfully completed standard ...201424698569
t cell response to alpha crystallin and mycobacterium tuberculosis specific antigens using ex-vivo elispot assay for detecting latent tuberculosis infection in addis ababa, ethiopia.mycobacterium tuberculosis (mtb) persists in a state of non-replication or stationary phase, but resulting in active tuberculosis (tb) when the immune system is suppressed. alpha-crystallin (acr) is one of the bacterial antigens characterized known to be related to shifting of the bacilli from growth to a non-replicating persistent state.201424696984
comparison of ligation-mediated pcr methods in differentiation of mycobacterium tuberculosis strains.fast and inexpensive identification of epidemiological links between limited number of mycobacterium tuberculosis strains is required to initially evaluate hospital outbreaks, laboratory crosscontaminations, and family or small community transmissions. the ligation-mediated pcr methods (lm-pcr) appear sufficiently discriminative and reproducible to be considered as a good candidate for such initial, epidemiological analysis. here, we compared the discriminative power of the recently developed in ...201424696162
a prospective study of the prevalence of tuberculosis and bacteraemia in bangladeshi children with severe malnutrition and pneumonia including an evaluation of xpert mtb/rif assay.severe malnutrition is a risk factor for pneumonia due to a wide range of pathogens but aetiological data are limited and the role of mycobacterium tuberculosis is uncertain.201424695758
immune subversion by mycobacterium tuberculosis through ccr5 mediated signaling: involvement of il-10.tuberculosis is characterized by severe immunosuppression of the host macrophages, resulting in the loss of the host protective immune responses. during mycobacterium tuberculosis infection, the pathogen modulates c-c chemokine receptor 5 (ccr5) to enhance il-10 production, indicating the possible involvement of ccr5 in regulation of the host immune response. here, we found that mycobacterium infection significantly increased ccr5 expression in macrophages there by facilitating the activation of ...201424695099
mycobacterium tuberculosis beijing family: analysis of the epidemiological and clinical factors associated with an emerging lineage in the urban area of milan.the mycobacterium tuberculosis beijing genotype raises major concern because of global spreading, hyper-virulence and association with multi-drug resistance (mdr). the aims of the study were to evaluate role of beijing family in the epidemiological setting of milan and to identify predictors associated with the spreading of this lineage. overall 3830tb cases were included. beijing family accounted for 100 isolates (2.6%). prevalence grew from 1.7% to 5.4% in the period 1996-2009. foreign origin ...201424694826
different phenotypes of cd8+ t cells associated with bacterial load in active tuberculosis.tuberculosis is an infectious disease that affects millions of people worldwide with an annual mortality rate of 1.3 million. the mechanisms contributing to the loss of balance of immune responses and progression to active tuberculosis disease are unknown. although cd4+ and cd8+ t cells and the cytokines they produce are crucial for protection against tuberculosis they have different roles in tuberculosis immunology. the function of cd4+ t cells has been extensively studied; however, less is kno ...201424694750
successful bilateral lung transplantation from a deceased donor with active mycobacterium tuberculosis infection.in the present report, we describe a case wherein a mycobacterium tuberculosis infection developed in the recipient after successful bilateral lung transplantation because of a solitary pulmonary nodule in the donor.201424694450
synthetic calanolides with bactericidal activity against replicating and nonreplicating mycobacterium tuberculosis.it is urgent to introduce new drugs for tuberculosis to shorten the prolonged course of treatment and control drug-resistant mycobacterium tuberculosis (mtb). one strategy toward this goal is to develop antibiotics that eradicate both replicating (r) and nonreplicating (nr) mtb. naturally occurring (+)-calanolide a was active against r-mtb. the present report details the design, synthesis, antimycobacterial activities, and structure-activity relationships of synthetic calanolides. we identified ...201424694175
simultaneous chylothorax and chylous ascites due to tuberculosis.chylothorax or chylous ascites is rare manifestation of tuberculosis. we report a case of simultaneous chylothorax and chylous ascites due to tuberculosis. a 17-year-old girl was admitted with fever, abdominal distention and dyspnea. chest and abdominal computed tomography revealed bilateral pleural effusion, multifocal nodular consolidation on both lung fields and copious ascites and multiple necrotic lymphadenopathy in the abdominal cavity. mycobacterium tuberculosis was isolated from sputum a ...201424693471
clinico-pathological features of tuberculosis due to mycobacterium tuberculosis uganda genotype in patients with tuberculous lymphadenitis: a cross sectional study.tuberculous lymphadenitis is next to pulmonary tuberculosis as the most common cause of tuberculosis. uganda genotype, one of the sub-lineages of mycobacterium tuberculosis, is the most prevalent cause of pulmonary tuberculosis in uganda. we here investigate the clinicopathological characteristics of patients with tuberculous lymphadenitis infected with m. tuberculosis uganda genotype compared with those infected with m. tuberculosis non-uganda genotype strains.201424690344
structural insight into how streptomyces coelicolor maltosyl transferase glge binds α-maltose 1-phosphate and forms a maltosyl-enzyme intermediate.glge (ec 2.4.99.16) is an α-maltose 1-phosphate:(1→4)-α-d-glucan 4-α-d-maltosyltransferase of the cazy glycoside hydrolase 13_3 family. it is the defining enzyme of a bacterial α-glucan biosynthetic pathway and is a genetically validated anti-tuberculosis target. it catalyzes the α-retaining transfer of maltosyl units from α-maltose 1-phosphate to maltooligosaccharides and is predicted to use a double-displacement mechanism. evidence of this mechanism was obtained using a combination of site-dir ...201424689960
human pleural b-cells regulate ifn-γ production by local t-cells and nk cells in a mycobacterium tuberculosis-induced delayed hypersensitivity reaction.dth (delayed type hypersensitivity) reactions are secondary cellular immune responses that appear 24-72 h after antigen exposure. tuberculous pleurisy is a common manifestation of extrapulmonary tb (tuberculosis) and is considered a human model of th1-mediated dth. in order to identify functional cross-talk among cellular populations sited in this inflammatory microenvironment, we analysed phenotypic and functional features of human b-cells isolated from the pf (pleural fluid) of tb patients. fr ...201424689690
intra-abdominal mycobacterium tuberculosis infection in a dog. 201724689658
mycobacterium tuberculosis belonging to family lam and sublineage rd(rio): common strains in southern brazil for over 10 years.a sublineage of mycobacterium tuberculosis called rd(rio) was described in 2007. although only recently described, this strain may have been present previously in the population, and its identification in clinical isolates will elucidate bacterial transmission dynamics and host-pathogen interactions. this study evaluated the clonal diversity of the rd(rio) sublineage in clinical isolates from rio grande-rs obtained between 1998 and 2001. among the 45 samples analyzed by the miru-vntr method, the ...201324688519
deoxysugars as antituberculars and alpha-mannosidase inhibitors.a promising modified sugar molecule was identified which was active against multidrug-resistant (mdr) strains of mycobacterium tuberculosis, suggesting involvement of a new target. the compound was demonstrated to be bactericidal, inhibited the growth of m. tuberculosis in mice, and targeted alpha-mannosidase as a competitive inhibitor with a ki value of 353.9 μm.201424687500
population pharmacokinetic/pharmacodynamic analysis of the bactericidal activities of sutezolid (pnu-100480) and its major metabolite against intracellular mycobacterium tuberculosis in ex vivo whole-blood cultures of patients with pulmonary tuberculosis.sutezolid (pnu-100480 [u-480]) is an oxazolidinone antimicrobial being developed for the treatment of tuberculosis. an active sulfoxide metabolite (pnu-101603 [u-603]), which reaches concentrations in plasma several times those of the parent, has been reported to drive the killing of extracellular mycobacterium tuberculosis by sutezolid in hollow-fiber culture. however, the relative contributions of the parent and metabolite against intracellular m. tuberculosis in vivo are not fully understood. ...201424687496
assessment of mycobacterium tuberculosis pantothenate kinase vulnerability through target knockdown and mechanistically diverse inhibitors.pantothenate kinase (pank) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme a (coa) biosynthesis. in our earlier reports, we had established that the type i isoform encoded by the coaa gene is an essential pantothenate kinase in mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of pank inhibitors. the present report summarizes the synt ...201424687493
using fluorescence correlation spectroscopy (fcs) for ifn-g detection: a preliminary study.nowadays, enzyme-linked immunosorbent assay (elisa) based detection of mycobacterium tuberculosis (m. tuberculosis) antigen triggered interferon-gamma (ifn-g) secretion by blood t cells displays an improved diagnostic value for m. tuberculosis infection. applications of fluorescence correlation spectroscopy (fcs) have been explored in various subfields of medicine and molecular biology, including detection of a certain biomarker in liquid instead of elisa. here, we present a preliminary study of ...201424685834
anti-rheumatoid and anti-oxidant activity of homeopathic guaiacum officinale in an animal model.homeopathy is a popular form of complementary and alternative medicine. guaiacum extract is said to be useful for pain and inflammation, but there appears to be no scientific evidence to support this.201424685418
lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the atp-dependent protease clpc1p1p2.languishing antibiotic discovery and flourishing antibiotic resistance have prompted the development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. here, we screen extracts from uncultured species against mycobacterium tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of m. tuberculosis, but little activity against other b ...201424684906
design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents.tuberculosis remains a global public health problem in recent years. to develop novel type of potential antitubercular agents, twelve novel dihydroartemisinin-fluoroquinolone (dha-fq) conjugates (three types of molecules) were gradually designed and conveniently synthesized. all the newly synthesized conjugates were well characterized and evaluated against different mycobacterium tuberculosis strains in vitro. the screening results showed that five dha-fq conjugates were active toward m. tubercu ...201424684842
interferon lambda-2 levels in sputum of patients with pulmonary mycobacterium tuberculosis infection.in humans, there are three members of type iii interferon family, designated as ifn-λ1 (il-29), ifn-λ2 (il-28a) and ifn-λ3 (il-28b). bacterial infections, including mycobacterium tuberculosis infection, trigger the expression of interferon i and ii genes, but little is known about their effect on ifn-λ genes. it has been found that m. tuberculosis infection in a549 lung epithelial cells stimulate upregulation of ifn-λ2 genes in vitro. the aim of this study was to determine the ifn-λ2 levels in s ...201424684674
the pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in asian elephants (elephas maximus).tuberculosis, caused by mycobacterium tuberculosis, is a disease of concern in captive asian elephants (elephas maximus). treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. in this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six asian elephants, and rectally to five elephants using a cross-over design. blood sa ...201424684601
the exochelins of pathogenic mycobacteria: unique, highly potent, lipid- and water-soluble hexadentate iron chelators with multiple potential therapeutic uses.exochelins are lipid- and water-soluble siderophores of mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena.201424684595
on the mechanism determining the th1/th2 phenotype of an immune response, and its pertinence to strategies for the prevention, and treatment, of certain infectious diseases.it is well recognized that the physiological/pathological consequences of an immune response, against a foreign or a self-antigen, are often critically dependent on the class of immunity generated. here we focus on how antigen interacts with the cells of the immune system to determine whether antigen predominantly generates th1 or th2 cells. we refer to this mechanism as the 'decision criterion' controlling the th1/th2 phenotype of the immune response. a plausible decision criterion should accou ...201424684592
assessment of messenger rna (mrna) of mycobacterium tuberculosis as a marker of cure in patients with pulmonary tuberculosis.to analyse the performance of rt-qpcr using 85b mrna in the diagnosis of mycobacterium tuberculosis infection and in the assessment of the response to treatment for pulmonary tuberculosis (tb).201424684542
pseudo-behçet's disease associated with tuberculosis: a case report and review of the literature.orogenital ulcer is one of the clinical manifestations of behçet's disease (bd). however, orogenital ulcer may be observed in various conditions, such as complex aphthous dermatitis and herpes simplex virus infections. therefore, orogenital ulcer along with skin lesions, including acne or erythema nodosum, may be misdiagnosed as bd, but is actually pseudo-bd instead. we report here a case of pseudo-bd due to mycobacterium tuberculosis infection in which anti-tuberculous treatment resulted in com ...201424682398
synthesis, characterization and pharmacological screening of some novel 5-imidazopyrazole incorporated polyhydroquinoline derivatives.a new category of polyhydroquinoline derivatives 8a-t were synthesized in moderate to good yield (64-85%) by one-pot three-component cyclocondensation reaction of 5-(1h-imidazol-1-yl)-3-methyl-1-phenyl-1h-pyrazole-4-carbaldehyde 3 with various enaminones 6a-h and different active methylene compounds (malononitrile 7a, ethylcaynoacetate 7b and caynoacetamide 7c) in absolute ethanol. the newly synthesized compounds were evaluated for their in vitro antimalarial activity against plasmodium falcipar ...201424681985
safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous tnf inhibitors.there is no consensus on whether restarting tnf inhibitors (tnfis) after treatment of an active tuberculosis (tb) infection caused by previous tnfi exposure is safe. in this study we sought to determine the safety of resuming tnfis in patients following tb treatment.201424681840
synthesis and anti-tuberculosis activity of the marine natural product caulerpin and its analogues.caulerpin (1a), a bis-indole alkaloid from the marine algal caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. the caulerpin analogues (1b-1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. the key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a-4g). all bis-indole compounds synthesized were evaluated against the mycobacterium tuberculosis strain h37rv, and ...201424681629
performance of symptom-based tuberculosis screening among people living with hiv: not as great as hoped.the objective of the present study was to determine the diagnostic performance of the symptom-based tuberculosis (tb) screening questionnaire recommended by who for people living with hiv (plwh) in resource-limited settings, among adults off and on antiretroviral therapy (art).201424681417
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