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molecular analysis of rv0679c and rv0180c genes of mycobacterium tuberculosis from clinical isolates of pulmonary tuberculosis.two novel proteins/genes rv0679c and rv0180c of mycobacterium tuberculosis (mtb) h37rv were classified as a hypothetical membrane and transmembrane proteins which might have a role in the invasion. molecular analysis of these genes in human clinical isolates of pulmonary tuberculosis (ptb) patients was not well characterised.201727934825
total synthesis of mycobacterium tuberculosis dideoxymycobactin-838 and stereoisomers: diverse cd1a-restricted t cells display a common hierarchy of lipopeptide recognition.mycobacterium tuberculosis produces dideoxymycobactin-838 (ddm-838), a lipopeptide that potently activates t cells upon binding to the mhc-like antigen-presenting molecule cd1a. m. tuberculosis produces ddm-838 in only trace amounts and a previous solid-phase synthesis provided sub-milligram quantities. we describe a high-yielding solution-phase synthesis of ddm-838 that features a mitsunobu substitution that avoids yield-limiting epimerization at lysine during esterification, and amidation cond ...201727925318
theoretical insights into the reaction and inhibition mechanism of metal-independent retaining glycosyltransferase responsible for mycothiol biosynthesis.understanding enzymatic reactions with atomic resolution has proven in recent years to be of tremendous interest for biochemical research, and thus, the use of qm/mm methods for the study of reaction mechanisms is experiencing a continuous growth. glycosyltransferases (gts) catalyze the formation of glycosidic bonds, and are important for many biotechnological purposes, including drug targeting. their reaction product may result with only one of the two possible stereochemical outcomes for the r ...201727935720
development of real-time immuno-pcr for the quantitative detection of mycobacterial psts1 in tuberculosis patients.a novel indirect real-time immuno-polymerase chain reaction (rt-i-pcr) assay, an evolution of i-pcr, was developed for the quantitative detection of mycobacterium tuberculosis psts1 (rv0934) with a wide dynamic range of 10ng/ml to 1pg/ml in body fluids of tuberculosis (tb) patients, which may monitor the dynamics of disease.201727940201
visualizing viable mycobacterium tuberculosis in sputum to monitor isolation measures. 201727939814
a multistrain mathematical model to investigate the role of pyrazinamide in the emergence of extensively drug-resistant tuberculosis.several infectious diseases of global importance-e.g., hiv infection and tuberculosis (tb)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. we used a multistrain model of ...201727956422
preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis.[purpose] multi-drug resistant (mdr), mycobacterium tuberculosis (tb) is a big problem in the world. we have developed novel tb therapeutic vaccine (hvj-e/hsp65 dna +il-12 dna). [methods and results] dna vaccine expressing tb heat shock protein 65 and il-12 was delivered by the hemagglutinating virus of japan (hvj)-envelope. this vaccine provided remarkable protective efficacy and strong therapeutic efficacy against mdr-tb and xdr-tb in murine models. furthermore, this vaccine provided therapeut ...201727960629
discovery and characterization of an f420-dependent glucose-6-phosphate dehydrogenase (rh-fgd1) from rhodococcus jostii rha1.cofactor f420, a 5-deazaflavin involved in obligatory hydride transfer, is widely distributed among archaeal methanogens and actinomycetes. owing to the low redox potential of the cofactor, f420-dependent enzymes play a pivotal role in central catabolic pathways and xenobiotic degradation processes in these organisms. a physiologically essential deazaflavoenzyme is the f420-dependent glucose-6-phosphate dehydrogenase (fgd), which catalyzes the reaction f420 + glucose-6-phosphate → f420h2 + 6-pho ...201727966048
vaccination for mycobacterium tuberculosis infection: reprogramming cd4 t-cell homing into the lung.development of effective tuberculosis vaccines is hampered by insufficient understanding of protective immunity. here, woodworth et al.(1) show secondary effector cd4 t cells generated after mtb challenge of h56/caf01 vaccinated mice display superior lung homing compared with primary effectors. vaccination generates large populations of parenchymal lung effector cells by inducing cxcr3(+)klrg1(-) cells that continuously migrate from lymph nodes to lung, and limiting the generation of non-protect ...201727966550
evaluation of the genotype mtbdrsl version 2.0 assay for second-line drug resistance detection of mycobacterium tuberculosis isolates in south africa.early detection of resistance to second-line antituberculosis drugs is important for the management of multidrug-resistant tuberculosis (mdr-tb). the genotype mtbdrsl version 2.0 (ver 2.0) line probe assay has been redesigned for molecular detection of resistance-conferring mutations of fluoroquinolones (flq) (gyra and gyrb genes) and second-line injectable drugs (slid) (rrs and eis genes). the study evaluated the diagnostic performance of the genotype mtbdrsl ver 2.0 assay for the detection of ...201727974543
structural basis for the species-selective binding of n,c-capped dipeptides to the mycobacterium tuberculosis proteasome.the mycobacterium tuberculosis (mtb) 20s proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. to qualify for drug development, inhibitors targeting mtb 20s must spare both the human constitutive proteasome (c-20s) and immunoproteasome (i-20s). we recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for mtb 20s over human c-20s and i-20s. to understand the structural ...201727976853
inhalation of respirable crystalline rifapentine particles induces pulmonary inflammation.rifapentine is an anti-tuberculosis (anti-tb) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. we have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. the delivery of crystalline particles to the lungs may promote inflammation. this in vivo study characterizes the inflammatory ...201727977216
exploring tuberculosis by molecular tests on dna isolated from smear microscopy slides.tuberculosis (tb) is an infectious disease of global public health importance caused by mycobacterium tuberculosis complex. the disease has worsened with the emergence of multidrug-resistant (mdr)-tb strains. the timely diagnosis and treatment of tb remains a key public health priority, and laboratories have a critical role in the rapid and accurate detection of tb and drug resistance. molecular assays based on nucleic acid amplification techniques have been developed for the rapid, sensitive, a ...201727979786
inhibitors of mycobacterium tuberculosis dosrst signaling and persistence.the mycobacterium tuberculosis (mtb) dosrst two-component regulatory system promotes the survival of mtb during non-replicating persistence (nrp). nrp bacteria help drive the long course of tuberculosis therapy; therefore, chemical inhibition of dosrst may inhibit the ability of mtb to establish persistence and thus shorten treatment. using a dosrst-dependent fluorescent mtb reporter strain, a whole-cell phenotypic high-throughput screen of a ∼540,000 compound small-molecule library was conducte ...201727992879
synthesis and characterization of acetylated amylose and development of inclusion complexes with rifampicin.amylose (am) tends to form single helical inclusion complexes with suitable agents. these complexes are considered promising biomaterial carrier since the guest molecules can be released later, leading to many applications, especially in the pharmaceutical industry. rifampicin (rif) has long been recognized as an active drug against mycobacterium tuberculosis, however, the administration of rif in high dosages can originate unwanted side-effects. due to the fact that the use of native amylose (a ...201727987927
mycobacterium tuberculosis pe_pgrs18 enhances the intracellular survival of m. smegmatis via altering host macrophage cytokine profiling and attenuating the cell apoptosis.mycobacterium tuberculosis pe/ppe family proteins, named after the presence of conserved pe (pro-glu) and ppe (pro-pro-glu) domains at n-terminal, are prevalent in m. tuberculosis genome. the function of most pe/ppe family proteins remains elusive. to characterize the function of pe_pgrs18, the encoding gene was heterologously expressed in m. smegmatis, a nonpathogenic mycobacterium. the recombinant pe_pgrs18 is cell wall associated. m. smegmatis pe_pgrs18 recombinant showed differential respons ...201727987050
removing the bottleneck in whole genome sequencing of mycobacterium tuberculosis for rapid drug resistance analysis: a call to action.whole genome sequencing (wgs) can provide a comprehensive analysis of mycobacterium tuberculosis mutations that cause resistance to anti-tuberculosis drugs. with the deployment of bench-top sequencers and rapid analytical software, wgs is poised to become a useful tool to guide treatment. however, direct sequencing from clinical specimens to provide a full drug resistance profile remains a serious challenge. this article reviews current practices for extracting m. tuberculosis dna and possible s ...201727986491
mycobacterium tuberculosis is selectively killed by rifampin and rifapentine in hypoxia at neutral ph.the activities of rifampin, rifapentine, bedaquiline, pa-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) mycobacterium tuberculosis h37rv under conditions of hypoxia at phs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. at ph 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. at ph 7.3, only rifampin an ...201727993848
the presence of non-native helical structure in the unfolding of a beta-sheet protein mpt63.mpt63, a major secreted protein from mycobacterium tuberculosis, has been shown to have immunogenic properties and has been implicated in virulence. mpt63 is a β-sandwich protein containing 11 β strands and a very short stretch of 310 helix. the detailed experimental and computational study reported here investigates the equilibrium unfolding transition of mpt63. it is shown that in spite of being a complete β-sheet protein, mpt63 has a strong propensity toward helix structures in its early inte ...201727997710
resistance of mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones - authors' reply. 201727998569
resistance of mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones. 201727998568
matrix-assisted laser desorption ionization-time of flight mass spectrometry for combined species identification and drug sensitivity testing in mycobacteria.species identification and drug susceptibility testing (dst) of mycobacteria are important yet complex processes traditionally reserved for reference laboratories. recent technical improvements in matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof ms) has started to facilitate routine mycobacterial identifications in clinical laboratories. in this paper, we investigate the possibility of performing phenotypic maldi-based dst in mycobacteriology using the rece ...201728003422
spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models.new drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (tb) in humans. the spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by mycobacterium tuberculosis . spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. here we explore the in vivo activity of lead spectinamides when co ...201727999020
novel rapid pcr for the detection of ile491phe rpob mutation of mycobacterium tuberculosis, a rifampicin-resistance-conferring mutation undetected by commercial assays.neither the liquid medium-based bactec mgit, nor commercial molecular assays such as the xpert mtb/rif and the mtbdrplus v2.0 assays are capable of detecting up to 30% of rifampicin-resistant mycobacterium tuberculosis strains in swaziland because of the large proportion of the rpob ile491phe mutations. in other countries, the frequency of this mutation is thought to be low.201727998822
tuberculosis cases caused by heterogeneous infection in eastern europe and their influence on outcomes.mycobacterium tuberculosis superinfection is known to occur in areas with high rates of tuberculosis (tb) and has a significant impact on overall clinical tb management.201727998730
trends in testing for mycobacterium tuberculosis complex from us public health laboratories, 2009-2013.we investigated data from us public health laboratories funded through the centers for disease control and prevention's tuberculosis elimination and laboratory cooperative agreement to document trends and challenges in meeting national objectives in tuberculosis (tb) laboratory diagnoses.201728005481
a brief primer on genomic epidemiology: lessons learned from mycobacterium tuberculosis.genomics is now firmly established as a technique for the investigation and reconstruction of communicable disease outbreaks, with many genomic epidemiology studies focusing on revealing transmission routes of mycobacterium tuberculosis. in this primer, we introduce the basic techniques underlying transmission inference from genomic data, using illustrative examples from m. tuberculosis and other pathogens routinely sequenced by public health agencies. we describe the laboratory and epidemiologi ...201728009051
modulatory effect of standardised amentoflavone isolated from juniperus communis l. agianst freund's adjuvant induced arthritis in rats (histopathological and x ray anaysis).juniperus communis. l. is a shrub or small evergreen tree, native to europe, south asia, and north america, and belongs to family cupressaceae. it has been used traditionally in unani system and in swedish medicine as a decoction in inflammatory diseases. the main chemical constituents, which were reported in j. communis l. was α-pinene,, apigenin, sabinene, β-sitosterol, campesterol, limonene, amentoflavone (af), cupressuflavone, and many others.201728012393
overexpression of rv2788 increases mycobacterium stresses survival.mycobacterium tuberculosis, the causative agent of tuberculosis-one of the most devastating infectious diseases, is a successful intracellular pathogen capable of surviving diverse stresses. unveiling the molecular mechanisms governing this superior adaptation will inspire better control measures against tuberculosis. to define the role of rv2788, a manganese-dependent transcriptional repressor, m.smegmatis was used as the host strain for heterologous expression rv2788. rv2788 can significantly ...201728024526
isolated tubercular osteomyelitis of acromion: a case report and review of literature.tuberculosis is an infectious disease of public health interest, infecting one-third of the world population. up to 3% of all tubercular cases have musculoskeletal involvement with less than 1% involving the scapular. to the best of our knowledge, we present the third case of acromion involvement in reported literature. an adolescent female with complains of shoulder pain with no restriction of movements, no local symptoms, no fever, no history of tuberculosis was being treated on analgesics for ...201728018073
the ubiquitin ligase smurf1 functions in selective autophagy of mycobacterium tuberculosis and anti-tuberculous host defense.during antibacterial autophagy, ubiquitination of intracellular bacteria recruits proteins that mediate bacterial delivery to the lysosome for degradation. smurf1 is an e3 ubiquitin ligase whose role in selective bacterial autophagy is unknown. we show that smurf1 facilitates selective autophagy of the human pathogen mycobacterium tuberculosis (mtb). smurf1(-/-) macrophages are defective in recruiting polyubiquitin, the proteasome, the ubiquitin-binding autophagy adaptor nbr1, the autophagy prot ...201728017659
[spanish network for the study of paediatric tuberculosis. at the forefront of europe]. 201728025972
synthesis and anti-mycobacterial activity of 4-(4-phenyl-1h-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug.the antitubercular drug; para-aminosalicylic acid (pas) was used as the core scaffold for the design of a series of 1h-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. the obtained derivatives were screened against mycobacterium tuberculosis h37rv revealing good to high activity for the active compounds (mic values of 0.39-1.5 μg/ml) compared to the marketed drugs isoniazid, rifampicin and ethambutol. moreover, the ...201728028696
a novel motif for s-adenosyl-l-methionine binding by the ribosomal rna methyltransferase tlya from mycobacterium tuberculosis.capreomycin is a potent ribosome-targeting antibiotic that is an essential component of current antituberculosis treatments, particularly in the case of multidrug-resistant mycobacterium tuberculosis (mtb). optimal capreomycin binding and mtb ribosome inhibition requires ribosomal rna methylation in both ribosome subunits by tlya (rv1694), an enzyme with dual 2'-o-methytransferase and putative hemolytic activities. despite the important role of tlya in capreomycin sensitivity and identification ...201728031456
[the expression of t-bet is negatively correlated with the expressions of ifn-γ and tnf-α in cd4(+) t cells of patients with active pulmonary tuberculosis].objective to investigate the relationship between t box expressed in t cells (t-bet) and the production of interferon γ (ifn-γ), tumor necrosis factor α (tnf-α) and interleukin 2 (il-2) in cd4(+)t cells of patients with active pulmonary tuberculosis. methods peripheral blood mononuclear cells (pbmcs) were isolated from peripheral blood by density gradient centrifugation. individuals with latent mycobacterium tuberculosis (mtb) infection were screened by enzyme-linked immunospot assay (elispot). ...201728031119
prevalence of latent tuberculosis infection among tuberculosis laboratory workers in iran.the risk of transmission of mycobacterium tuberculosis from patients to health care workers (hcws) is a neglected problem in many countries, including iran. the aim of this study was to estimate the prevalence of latent tuberculosis (tb) infection (ltbi) among tb laboratory staff in iran, and to elucidate the risk factors associated with ltbi.201728092930
genomic analysis of globally diverse mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.multidrug-resistant tuberculosis (mdr-tb), caused by drug-resistant strains of mycobacterium tuberculosis, is an increasingly serious problem worldwide. here we examined a data set of whole-genome sequences from 5,310 m. tuberculosis isolates from five continents. despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. we have identified harbin ...201728092681
performance of nested multiplex pcr assay targeting mtp40 and is6110 gene sequences for the diagnosis of tubercular lymphadenitis.the conventional methods for diagnosis of tubercular lymphadenitis (tbln) such as - fine needle aspiration cytology, ziehl-neelsen staining and culture have limitations of low sensitivity and/or specificity. so, it becomes essential to develop a rapid, sensitive, and specific method for an early diagnosis of tbln. therefore, the present study was conducted to evaluate nested multiplex polymerase chain reaction (nmpcr) targeting mtp40 and is6110 gene sequences of mycobacterium tuberculosis and my ...201728035600
pros and cons of direct genotyping on tuberculosis clinical samples.prompt genotyping of mycobacterium tuberculosis (m. tuberculosis) is crucial for improving molecular epidemiological investigation of tuberculosis (tb).201728034830
immune reconstitution inflammatory syndrome associated with pulmonary pathogens.immune reconstitution inflammatory syndrome (iris) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in hiv-infected patients. although iris can occur in many organs, pulmonary iris, associated with opportunistic infections such as mycobacterium tuberculosis and pneumocystis jirovecii, is particularly associated with high morbidity and mortality. the pathology of iris is associated with a variety of innate and ...201728049128
human and mouse hematopoietic stem cells are a depot for dormant mycobacterium tuberculosis.an estimated third of the world's population is latently infected with mycobacterium tuberculosis (mtb), with no clinical signs of tuberculosis (tb), but lifelong risk of reactivation to active disease. the niches of persisting bacteria during latent tb infection remain unclear. we detect mtb dna in peripheral blood selectively in long-term repopulating pluripotent hematopoietic stem cells (lt-phscs) as well as in mesenchymal stem cells from latently infected human donors. in mice infected with ...201728046053
c-type lectin receptor dcir modulates immunity to tuberculosis by sustaining type i interferon signaling in dendritic cells.immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. tuberculosis (tb) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. here, we report that c-type lectin dendritic cell (dc) immunoreceptor (dcir), a key component in dc homeostasis, is required to modulate lung infl ...201728069953
interaction of the cd43 sialomucin with the mycobacterium tuberculosis cpn60.2 chaperonin leads to tumor necrosis factor alpha production.mycobacterium tuberculosis is the causal agent of tuberculosis. tumor necrosis factor alpha (tnf-α), transforming growth factor β (tgf-β), and gamma interferon (ifn-γ) secreted by activated macrophages and lymphocytes are considered essential to contain mycobacterium tuberculosis infection. the cd43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin cpn60.2, facilitating mycobacterium-macrophage contact. we report here that cpn60.2 induces b ...201728069816
mutation in an unannotated protein confers carbapenem resistance in mycobacterium tuberculosis.β-lactams are the most widely used antibacterials. among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. as recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before mycobacterium tuberculosis strains resistant to these drugs will emerge. in the present study, we investigated the genetic basis that confers such resistance. to our surprise, instead of mutations in ...201728069655
antituberculosis compounds from a deep-sea-derived fungus aspergillus sp. scsio ind09f01.eleven diketopiperazine and fumiquinazoline alkaloids (1-11) together with a tetracyclic triterpenoid helvolic acid (12) were obtained from the cultures of a deep-sea derived fungus aspergillus sp. scsio ind09f01. the structures of these compounds (1-12) were determined mainly by the extensive nmr, esims spectra data and by comparison with previously described compounds. besides, anti-tuberculosis, cytotoxic, antibacterial, cox-2 inhibitory and antiviral activities of these compounds were evalua ...201728068839
diagnosis of opportunistic infections: hiv co-infections - tuberculosis.tuberculosis (tb) incidence has declined ∼1.5% annually since 2000, but continued to affect 10.4 million individuals in 2015, with 1/3 remaining undiagnosed or underreported. the diagnosis of tb among those co-infected with hiv is challenging as tb remains the leading cause of death in such individuals. accurate and rapid diagnosis of active tb will avert mortality in both adults and children, reduce transmission, and assist in timeous decisions for antiretroviral therapy initiation. this review ...201728059955
[cytokine neutralization at specific cellular source : a new therapeutic paradigm? german version].currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. this approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine.201728058501
mycobacterium tuberculosis protease marp activates a peptidoglycan hydrolase during acid stress.mycobacterium tuberculosis (mtb) can persist in the human host in a latent state for decades, in part because it has the ability to withstand numerous stresses imposed by host immunity. prior studies have established the essentiality of the periplasmic protease marp for mtb to survive in acidified phagosomes and establish and maintain infection in mice. however, the proteolytic substrates of marp that mediate these phenotypes were unknown. here, we used biochemical methods coupled with supravita ...201728057704
preparation and biological evaluation of ethionamide-mesoporous silicon nanoparticles against mycobacterium tuberculosis.ethionamide (eth) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant mycobacterium tuberculosis. recently, we reported that the loading of eth into thermally carbonized-porous silicon (tcpsi) nanoparticles enhanced the solubility and permeability of eth at different ph-values and also increased its metabolization process. based on these results, we synthesized carboxylic acid functionalized thermally hydrocarbonized porous silic ...201728057421
rifampicin-resistance pattern of mycobacterium tuberculosis and associated factors among presumptive tuberculosis patients referred to debre markos referral hospital, ethiopia: a cross-sectional study.prevailing data on rifampicin-resistant m. tuberculosis is essential for early management of mdr-tb. therefore, this study was conducted to determine the prevalence of rifampicin-resistant mycobacterium tuberculosis and associated factors among presumptive tb cases in debre markos referral hospital, ethiopia.201728057041
the crystal structure of pkni from mycobacterium tuberculosis shows an inactive, pseudokinase-like conformation.eukaryotic-like ser/thr protein kinases (epks) have been identified in many bacterial species, where they are known to mediate signalling mechanisms that share several features with their eukaryotic counterparts. in mycobacterium tuberculosis, pkni is one of the 11 predicted epks and it has been related to bacterial virulence. in order to better understand the molecular basis of its role in mycobacterial signalling, we solved the crystal structure of the pkni cytoplasmic domain. we found that ev ...201728054744
official american thoracic society/infectious diseases society of america/centers for disease control and prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.individuals infected with mycobacterium tuberculosis (mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [ltbi]). tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain.201728052967
subcellular partitioning and intramacrophage selectivity of antimicrobial compounds against mycobacterium tuberculosis.the efficacy of antimicrobial drugs against mycobacterium tuberculosis, an intracellular bacterial pathogen, is generally first established by testing compounds against bacteria in axenic culture. however, inside infected macrophages, bacteria encounter an environment which differs substantially from broth culture and are subject to important host-dependent pharmacokinetic phenomena which modulate drug activity. here, we describe how ph-dependent partitioning drives asymmetric antimicrobial drug ...201728052847
saxifragifolin d attenuates phagosome maturation arrest in mycobacterium tuberculosis-infected macrophages via an ampk and vps34-dependent pathway.saxifragifolin d (sd), a traditional chinese medicine, is a pentacyclic triterpenoid compound first isolated from androsace umbellata. various plant triterpenoids have been reported to exhibit antitubercular activity. in this study, thp-1-derived macrophages were infected with an attenuated m. tuberculosis (m.tb) strain, h37ra. intracellular replication of m.tb was evaluated by counting the colonies after 4 weeks of incubation. the results indicated that sd treatment reduced the intracellular re ...201728050854
t cell responses and regulation and the impact of in vitro il-10 and tgf-β modulation during treatment of active tuberculosis.mycobacterium tuberculosis (mtb) is particularly challenging for the immune system being an intracellular pathogen, and a variety of t cell subpopulations are activated by the host defence mechanism. in this study, we investigated t cell responses and regulation in active tb patients with drug-sensitive mtb (n = 18) during 24 weeks of efficient anti-tb therapy. t cell activation, differentiation, regulatory t cell (treg) subsets, mtb-induced t cell proliferation and in vitro il-10 and tgf-β modu ...201727862137
molecular, spatial, and field epidemiology suggesting tb transmission in community, not hospital, gaborone, botswana.during 2012-2015, 10 of 24 patients infected with matching genotypes of mycobacterium tuberculosis received care at the same hospital in gaborone, botswana. nosocomial transmission was initially suspected, but we discovered plausible sites of community transmission for 20 (95%) of 21 interviewed patients. active case-finding at these sites could halt ongoing transmission.201727869604
double-blind, placebo-controlled, 1:1 randomized phase iii clinical trial of immunoxel honey lozenges as an adjunct immunotherapy in 269 patients with pulmonary tuberculosis.safer and shorter antituberculosis treatment (att) regimens represent the unmet medical need.201727868466
paradoxical results of two automated real-time pcr assays in the diagnosis of pleural tuberculosis.tuberculosis (tb) is a major cause of worldwide mortality. we report the case of a non-hiv-infected woman with clinical suspicion of pleural tuberculosis and contradictory results between xpert(®) mtb/rif and abbott realtime mtb assays from pleural fluid specimen. liquid and solid cultures for tuberculosis were performed with negative results. the patient received treatment, and clinical improvement was observed. both techniques detect mycobacterium tuberculosis complex, but they have different ...201727866961
missense mutations in the unfoldase clpc1 of the caseinolytic protease complex are associated with pyrazinamide resistance in mycobacterium tuberculosis.previously, we showed that mutations in mycobacterium tuberculosis pand, involved in coenzyme a biosynthesis, cause resistance against pyrazinoic acid, the bioactive component of the prodrug pyrazinamide. to identify additional resistance mechanisms, we isolated mutants resistant against pyrazinoic acid and subjected pand wild-type strains to whole-genome sequencing. eight of the nine resistant strains harbored missense mutations in the unfoldase clpc1 associated with the caseinolytic protease c ...201727872068
preventive therapy for latent tuberculosis infection-the promise and the challenges.around one third of the world's population may harbour latent tuberculosis infection (ltbi), an asymptomatic immunological state that confers a heightened risk of subsequently developing tuberculosis (tb). effectively treating ltbi will be essential if the end tb strategy is to be realized. this review evaluates the evidence in relation to the effectiveness of preventive antibiotic therapy to treat ltbi due to both drug-susceptible and drug-resistant bacteria. current national and international ...201727872018
biomarkers for discrimination between latent tuberculosis infection and active tuberculosis disease.we aimed to determine whether combinations of multiplex cytokine responses could differentiate mycobacterium tuberculosis (mtb) infection states.201727871809
pott's disease: a major issue for an unaccompanied refugee minor.the incidence of tb in children in germany has been on a rise since 2008, especially among foreign-born individuals. with rapidly increasing numbers of refugees from the numerous areas of conflict, this increase in incidence is not expected to halt, neither in germany nor in europe in general. we report a case of insufficient tracking in a 16-year-old unaccompanied refugee minor from somalia who had a positive interferon γ release assay on arrival in germany. no actions were undertaken, until 6  ...201727872320
potential effect of ezetimibe against mycobacterium tuberculosis infection in type ii diabetes.tuberculosis (tb) risk might be increased in patients with diabetes by factors other than hyperglycaemia, such as dyslipidaemia. host lipids are essential energy sources used by mycobacteria to persist in a latent tb state. a potential therapy targeting cholesterol catabolism of mycobacteria has been proposed, but the potential of cholesterol-lowering drugs as anti-tb therapy is unclear. the purpose of this study was to determine the effects of ezetimibe, a 2-azetidinone cholesterol absorption i ...201727879023
recent developments in natural product-based drug discovery for tuberculosis.natural products (nps) have been at the origin of several established drugs against tuberculosis (tb). although the current clinical tb pipeline does not feature any candidates derived from new np scaffolds, numerous novel nps or np analogs have been discovered in the recent past with promising activity against mycobacterium tuberculosis (mtb). this includes newly discovered structures as well as known np classes that had not been previously recognized to be active against mtb. these compounds c ...201727890820
cough and fever in an immigrant adolescent with abnormal chest x-ray.tuberculosis (tb) remains a leading cause of death from infectious disease worldwide with 80,000 pediatric deaths annually. disease caused by mycobacterium tuberculosis (mtb) is usually asymptomatic in pediatric patients and resolves after completion of standard therapy with isoniazid (inh). rare reports document children greater than 10 years of age in endemic regions developing adult type cavitary disease, an infectious pulmonary tuberculosis lesion. this is a notable case of post-infectious p ...201727882294
a polymorphism in human mr1 is associated with mrna expression and susceptibility to tuberculosis.the mr1 antigen-presenting system is conserved among mammals and enables t cells to recognize small molecules produced by bacterial pathogens, including mycobacterium tuberculosis (m.tb). however, it is not known whether mr1-mediated antigen presentation is important for protective immunity against mycobacterial disease. we hypothesized that genetic control of mr1 expression correlates with clinical outcomes of tuberculosis infection. we performed an mr1 candidate gene association study and iden ...201727881839
the c-terminal extension of mycobacterium tuberculosis hsp16.3 regulates its oligomerization, subunit exchange dynamics and chaperone function.mycobacterium tuberculosis is a human pathogen that secretes a major immunodominant antigen, namely hsp16.3, throughout the course of infection. hsp16.3 belongs to the small heat shock protein family and exhibits a molecular chaperone function that is important for the growth and survival of m. tuberculosis in host cell macrophages. the importance of the n-terminal region for the structure and chaperone function of hsp16.3 is well understood. however, the effect of the c-terminal region on these ...201727885799
therapeutic effects of traditional chinese medicine niubeixiaohe in mouse tuberculosis models.the traditional chinese medicine niubeixiaohe (nbxh) is an effective anti-tuberculosis prescription, which is made up of bulbus fritillariae cirrhosae, rhizoma bletillae, radix platycodonis, fructus arctii, herba houttuyniae and glutinous rice. in this study, nbxh powder (i) and three kinds of nbxh extracts (ii, iii, and iv) were prepared. the water decoction of nbxh had been used to treat tb in clinic sixteen years suggested that it was effective to treat tb.201727884716
natural terpenes influence the activity of antibiotics against isolated mycobacterium tuberculosis.in this study, we aimed to describe the influence of natural terpenes on the antimycobacterial activity of first-line tuberculostatic drugs against isolated mycobacterium tuberculosis.201727883995
[first clinical isolate of mycobacterium tuberculosis exhibiting resistance to rifampicin and sensibility to isoniazid in the elche´s health department-general hospital(1998-2015)]. 201727883163
recognition of mycobacterial lipids by immune receptors.mycobacterium tuberculosis (mtb), the causative agent of tuberculosis (tb), infects one-third of the world's population and causes 1.5 million deaths each year. the cell envelopes of mycobacteria comprise a wealth of unique glycolipids, including trehalose-6,6'-dimycolate (tdm), lipoarabinomannan (lam), lipomannan (lm), and phosphatidylinositol (pi) mannosides (pims). these lipids are important modulators of the host immune responses during infection and in some cases have been used as adjuvants ...201727889398
modified protocol for drug susceptibility testing of mgit cultures of mycobacterium tuberculosis by the mgit 960.a rapid detection of resistance in mycobacterium tuberculosis is crucial for management and control of tuberculosis. this study evaluated a more rapid and cost-effective drug susceptibility testing (dst) protocol using primary isolates of m. tuberculosis in mycobacteria growth indicator tube (mgit). ninety-four m. tuberculosis isolates in mgit were subjected to dst by the manufacturer's method, i.e., primary isolates were subcultured and dst was performed from positive cultures for a maximum of ...201727889251
a short history of phototherapy, vitamin d and skin disease.the earliest record between sun exposure and skin disease goes back five millennia to the ancient egyptians. the modern scientific era of medical light therapy and skin diseases started in 1877 when downs and blunt reported that exposure to light inhibited fungal growth in test tubes. continuing research generated a growing medical interest in the potential the effects of light to treat and cure skin diseases considered as parasitic. this culminated in the awarding of the 1903 nobel prize in med ...201727892584
drug discovery targeting heme-based sensors and their coupled activities.heme-based sensors have emerged during the last 20years as being a large family of proteins that occur in all kingdoms of life. a myriad of biological adaptations are associated with these sensors, which include vasodilation, bacterial virulence, dormancy, chemotaxis, biofilm formation, among others. due to the key activities regulated by these proteins along with many other systems that use similar output domains, there is a growing interest in developing small molecules as their regulators. he ...201727893989
molecular investigation of resistance to second-line injectable drugs in multidrug-resistant clinical isolates of mycobacterium tuberculosis in france.the second-line injectable drugs (slid, i.e., amikacin, kanamycin, capreomycin) are key drugs for the treatment of multidrug-resistant tuberculosis. mutations in rrs region 1400, tlya, and eis promoter are associated with resistance to slid, to capreomycin, and to kanamycin, respectively. in this study, the sequencing data of slid resistance-associated genes were compared to the results of phenotypic drug susceptibility testing by the proportion method for the slid in 206 multidrug-resistant cli ...201727895017
de novo emergence of genetically resistant mutants of mycobacterium tuberculosis from the persistence phase cells formed against antituberculosis drugs in vitro.bacterial persisters are a subpopulation of cells that can tolerate lethal concentrations of antibiotics. however, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell populations, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. in the present study, we found that mycobacterium tuberculosis cells exposed continuously to lethal concentrations of rifampin (rif) or moxifloxacin (mxf) for prolonged durations showed kil ...201727895008
synthesis, screening and docking analysis of hispolon analogs as potential antitubercular agents.a series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. these compounds were subjected to in vitro antitubercular activity screening against mycobacterium tuberculosis (h37rv) strain. the synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6μg/ml. among the screened compounds, four compounds (h1, h2, h3 and h15) have shown moderate activity with mic 25μg/ml. potent activities were observed for the dihydrohispolon derivative h14 ...201727894872
whole-genome sequencing of mycobacterium tuberculosis provides insight into the evolution and genetic composition of drug-resistant tuberculosis in belarus.the emergence and spread of drug-resistant mycobacterium tuberculosis (dr-tb) are critical global health issues. eastern europe has some of the highest incidences of dr-tb, particularly multidrug-resistant (mdr) and extensively drug-resistant (xdr) tb. to better understand the genetic composition and evolution of mdr- and xdr-tb in the region, we sequenced and analyzed the genomes of 138 m. tuberculosis isolates from 97 patients sampled between 2010 and 2013 in minsk, belarus. mdr and xdr-tb iso ...201727903602
true rifampicin resistance missed by the mgit: prevalence of this pheno/genotype in the uk and ireland after 18 month surveillance.to characterize rifampicin-resistant strains missed by the mycobacteria growth indicator tube (mgit) 960 system but not by egg-based media in the uk and ireland and to ascertain their prevalence.201727903459
s-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents.two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1h-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. these compounds possessed excellent activity against mycobacterium tuberculosis, including the clinically isolated multidrug (mdr) and extensively drug-resistant (xdr) strains, with no cross resistance with first or second-line anti-tb drugs. the minimum inhibitory concentration ...201727907875
evaluation of the genexpert mtb/rif assay on extrapulmonary and respiratory samples other than sputum: a low burden country experience.the aim of this study was to assess the performance of the genexpert mtb/rif assay on extrapulmonary (ep) and respiratory (non-sputum) clinical samples of patients suspected of having tuberculosis (tb) from queensland, australia. a total of 269 ep and respiratory (non-sputum) clinical samples collected from qld patients who were suspected of having tb were subjected to the genexpert mtb/rif analysis, ziehl-neelsen (zn) staining, mycobacterium tuberculosis (mtb) culture and drug susceptibility te ...201727913043
the management of infection with mycobacterium tuberculosis in young children post-2015: an opportunity to close the policy-practice gap.the treatment of infection with mycobacterium tuberculosis in young children is supported by universal policy based on strong rationale and evidence of effectiveness, but has rarely been implemented in tuberculosis endemic countries. areas covered: this review highlights a number of important recent developments that provide an unprecedented opportunity to close the policy-practice gap, as well as ongoing needs to facilitate implementation under programmatic conditions and scale-up. expert comme ...201727910720
[tuberculosis among chronic hemodialysis patients in togo: report of 10 cases].to determine the frequency of tuberculosis among hemodialysis patients in togo, specify its different localizations and identify its diagnostic and therapeutic difficulties.201727843013
disseminated mycobacterium tuberculosis infection masquerading as metastasis after heavy ion radiotherapy for prostate cancer.fluorodeoxyglucose (fdg)-positron emission tomography with computed tomography (fdg-pet/ct) is useful in disease monitoring of malignancies after therapy, while an fdg uptake may also be present in benign diseases. we herein demonstrate a case of disseminated mycobacterium tuberculosis mimicking systemic metastasis of prostate cancer. this case highlights that clinicians should consider mycobacterium tuberculosis in patients with prostate cancer who demonstrate multifocal fdg uptakes masqueradin ...201727853089
dna topoisomerase i and dna gyrase as targets for tb therapy.tuberculosis (tb) is the deadliest bacterial disease in the world. new therapeutic agents are urgently needed to replace existing drugs for which resistance is a significant problem. dna topoisomerases are well-validated targets for antimicrobial and anticancer chemotherapies. although bacterial topoisomerase i has yet to be exploited as a target for clinical antibiotics, dna gyrase has been extensively targeted, including the highly clinically successful fluoroquinolones, which have been utiliz ...201727856347
drug targeting of heme proteins in mycobacterium tuberculosis.tb, caused by the human pathogen mycobacterium tuberculosis (mtb), causes more deaths than any other infectious disease. iron is crucial for mtb to infect the host and to sustain infection, with mtb encoding large numbers of iron-binding proteins. many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. various heme enzymes in mtb are validated drug targets and/or products ...201727856345
inflammatory properties and adjuvant potential of synthetic glycolipids homologous to mycolate esters of the cell wall of mycobacterium tuberculosis.the cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (mas; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). studies using mutant mtb strains have shown that the structure of mas influences the inflammatory potential of these glycolipids. as mutant mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the mtb cell wall using 38 differen ...201727855374
espc forms a filamentous structure in the cell envelope of mycobacterium tuberculosis and impacts esx-1 secretion.pathogenicity of mycobacterium tuberculosis (m. tb) is mediated by the esx-1 secretion system, which exports esxa and esxb, the major virulence factors that are co-secreted with espa and espc. functional information about esx-1 components is scarce. here, it was shown that espc associates with espa in the cytoplasm and membrane, then polymerizes during secretion from m. tb. espc was localized by immuno-gold electron microscopy in whole cells or cryosections as a surface-exposed filamentous struc ...201727859904
discovery of the type vii esx-1 secretion needle?mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five esat-6/type vii secretion (esx/t7s) systems. the first esx gene clusters were identified during the genome-sequencing project of m. tuberculosis h37rv. follow-up studies revealed additional genes playing important roles in esx/t7s systems. among the latter genes, one can find those that encode pro-glu (pe) and pro-pro-glu (ppe) proteins as well as a gene cluster that is encoded >260 kb upstream of the esx-1 lo ...201727859892
lipopolysaccharide-primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms.exposure of bone-marrow-derived dendritic cells (bmdc) to high-dose ultrapure lipopolysaccharide for 24 hr (lps-primed bmdc) enhances their potency in preventing inter-photoreceptor retinoid binding protein: complete freund's adjuvant-induced experimental autoimmune uveoretinitis (eau). lps-primed bmdc are refractory to further exposure to lps (= endotoxin tolerance), evidenced here by decreased phosphorylation of tank-binding kinase 1, interferon regulatory factor 3 (irf3), c-jun n-terminal kin ...201727859049
sp110b controls host immunity and susceptibility to tuberculosis.how host genetic factors affect mycobacterium tuberculosis (mtb) infection outcomes remains largely unknown. sp110b, an ifn-induced nuclear protein, is the nearest human homologue to the mouse ipr1 protein that has been shown to control host innate immunity to mtb infection. however, the function(s) of sp110b remains unclear.201727858493
h1:ic31 vaccination is safe and induces long-lived tnf-α(+)il-2(+)cd4 t cell responses in m. tuberculosis infected and uninfected adolescents: a randomized trial.control of the tuberculosis epidemic requires a novel vaccine that is effective in preventing tuberculosis in adolescents, a key target population for vaccination against tb.201727866772
molecular basis of mycobacterial survival in macrophages.macrophages play an essential role in the immune system by ingesting and degrading invading pathogens, initiating an inflammatory response and instructing adaptive immune cells, and resolving inflammation to restore homeostasis. more interesting is the fact that some bacteria have evolved to use macrophages as a natural habitat and tools of spread in the host, e.g., mycobacterium tuberculosis (mtb) and some non-tuberculous mycobacteria (ntm). mtb is considered one of humanity's most successful p ...201727866220
mycobacterium tuberculosis drug-resistance testing: challenges, recent developments and perspectives.drug-resistance testing, or antimicrobial susceptibility testing (ast), is mandatory for mycobacterium tuberculosis in cases of failure on standard therapy. we reviewed the different methods and techniques of phenotypic and genotypic approaches. although multiresistant and extensively drug-resistant (mdr/xdr) tuberculosis is present worldwide, ast for m. tuberculosis (ast-mtb) is still mainly performed according to the resources available rather than the drug-resistance rates. phenotypic methods ...201727810467
high-content screening of raw actinomycete extracts for the identification of antituberculosis activities.the feasibility and relevance of screening a library of raw actinomycete extracts (ecum library) for the identification of antituberculosis activities was assessed on 11,088 extracts using a multiple-screening approach. each extract was first tested at two concentrations against noninfected macrophages as a control, then against mycobacterium tuberculosis growing in broth medium as well as infecting murine macrophages. the screening results indicated a library of good quality with an apparent lo ...201727810952
prevalence of latent mycobacterium tuberculosis infection in prisoners.to determine the prevalence of and the factors associated with latent mycobacterium tuberculosis infection (ltbi) in prisoners in the state of minas gerais, brazil.201727812634
non-classical transpeptidases yield insight into new antibacterials.bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. historically, the final steps of peptidoglycan synthesis are known to be carried out by d,d-transpeptidases, enzymes that are inhibited by the β-lactams, which constitute >50% of all antibacterials in clinical use. here, we show that the carbapenem subclass of β-lactams are distinctly effective not only because they inhibit d,d-transpeptidases and are poor substr ...201727820797
genomic polymorphisms in a laboratory isolate of mycobacterium tuberculosis reference strain h37rv (atcc27294).the complete genome sequence of mycobacterium tuberculosis reference strain h37rv (atcc27294) was determined on an isolate carried in our laboratory collection for almost 20 years and named h37rvsiena. dna sequence analysis showed that the genome of h37rvsiena was 4,410,911 bp in size and contained 101 genetic polymorphisms compared to h37rv: 83 single nucleotide polymorphisms, 10 insertions, and 8 deletions of which one was 617-bp long and seven ranged from 1 to 7 bp. comparison with the genome ...201727819398
mycobacterium tuberculosis: readouts of bacterial fitness and the environment within the phagosome.macrophages fulfill most of their microbicidal duties in their phagosomes following uptake of microbes. however, some microbes, such as mycobacterium tuberculosis, have evolved mechanisms to subvert the normal maturation process of their phagocytic compartment to limit the hostility of this environment. the experimental analysis of this process and its subsequent impact on bacterial fitness is technically demanding and has required the development of a broad range of readouts to correlate functi ...201727815891
growing and handling of mycobacterium tuberculosis for macrophage infection assays.macrophage survival assays are a critical component of any mycobacterium tuberculosis research program. here we describe the methods that we use routinely for infection of macrophages of various origins. the protocols are efficient, relatively simple and are accepted widely. we provide users with methods for the infection of small numbers of macrophages-more suitable for microscopy; and for larger numbers of macrophages-for flow cytometry analysis or extraction for biochemical characterization.201727815890
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