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structure-activity relationships of spectinamide antituberculosis agents: a dissection of ribosomal inhibition and native efflux avoidance contributions.spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the mycobacterium tuberculosis rv1258c efflux pump. this study explores the structure-activity relationships through analysis of 50 targeted spectinamides. compounds are evaluated for ribosomal translational inhibition, mic activity in rv1258c ef ...201728081607
diagnostic accuracy of genexpert mtb/rif assay in comparison to conventional drug susceptibility testing method for the diagnosis of multidrug-resistant tuberculosis.xpert mtb/rif assay is regarded as a great achievement of modern medicine for the rapid diagnosis of multidrug-resistant tuberculosis (mdr-tb). the main purpose of this study was to determine the performance of xpert mtb/rif assay compared to conventional drug susceptibility testing (dst) method for the diagnosis of mdr-tb. a comparative cross sectional study was carried out at german-nepal tuberculosis project, kathmandu, nepal, from april 2014 to september 2014. a total of 88 culture positive ...201728081227
assessment of a 96-well plate assay of quantitative drug susceptibility testing for mycobacterium tuberculosis complex in china.to evaluate the performance of the sensitire mycotb mic plate (mycotb) which could measure the twelve anti-tuberculosis drugs susceptibility on one 96-wells plate.201728081169
isoniazid: a review of characteristics, properties and analytical methods.isoniazid is a synthetic antimicrobial and one of the most important first-line drugs used in the treatment of tuberculosis. since it was introduced in the therapy in 1952, the drug remains at the front line of the antituberculosis treatment mainly due to its potency and high selectivity against mycobacterium tuberculosis. pharmaceutical analysis and therapeutic drug monitoring of isoniazid in both, pharmaceuticals and biological samples, plays an important role to comprehend aspects regarding t ...201728080136
the quantiferon-tb gold in-tube assay in neuro-ophthalmology.although quantiferon-tb gold in-tube (qft-git) testing is regularly used to detect infection with mycobacterium tuberculosis, its utility in a patient population with a low risk for tuberculosis (tb) has been questioned. the following is a cohort study analyzing the efficacy of qft-git testing as a method for detection of active tb disease in low-risk individuals in a neuro-ophthalmologic setting.201728079759
corrigendum: construction and application of a co-expression network in mycobacterium tuberculosis. 201728079164
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
il-37 confers protection against mycobacterial infection involving suppressing inflammation and modulating t cell activation.interleukin-37 (il-37), a novel member of the il-1 family, plays fundamental immunosuppressive roles by broadly reducing both innate inflammation and acquired immunity, but whether it is involved in the pathogenesis of tuberculosis (tb) has not been clearly elucidated. in this study, single nucleotide polymorphism (snp) analysis demonstrated an association of the genetic variant rs3811047 of il-37 with tb susceptibility. in line with previous report, a significant elevated il-37 abundance in the ...201728076390
biosynthesis of the methylthioxylose capping motif of lipoarabinomannan in mycobacterium tuberculosis.lipoarabinomannan (lam) is a lipoglycan found in abundant quantities in the cell envelope of all mycobacteria. the nonreducing arabinan termini of lam display species-specific structural microheterogeneity that impacts the biological activity of the entire molecule. mycobacterium tuberculosis, for instance, produces mannoside caps made of one to three α-(1 → 2)-manp-linked residues that may be further substituted with an α-(1 → 4)-linked methylthio-d-xylose (mtx) residue. while the biological fu ...201728075556
discovery of imidazo[1,2-a]pyridine ethers and squaramides as selective and potent inhibitors of mycobacterial adenosine triphosphate (atp) synthesis.the approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (atp) synthase as an attractive target to kill mycobacterium tuberculosis (mtb). herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (ipe) and squaramides (sqa) as inhibitors of mycobacterial atp synthesis. through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an atp synth ...201728075132
binding and processing of β-lactam antibiotics by the transpeptidase ldtmt2 from mycobacterium tuberculosis.β-lactam antibiotics represent a novel direction in the chemotherapy of tuberculosis that brings the peptidoglycan layer of the complex mycobacterial cell wall in focus as a therapeutic target. peptidoglycan stability in mycobacterium tuberculosis, especially during infection, relies on the nonconventional peptide cross-links formed by l,d-transpeptidases. these enzymes are known to be inhibited by β-lactams, primarily carbapenems, leading to a stable covalent modification at the enzyme active s ...201728075068
dynamics of fluoroquinolones induced resistance in dna gyrase of mycobacterium tuberculosis.dna gyrase is a validated target of fluoroquinolones which are key components of multidrug resistance tuberculosis (tb) treatment. most frequent occurring mutations associated with high level of resistance to fluoroquinolone in clinical isolates of tb patients are a90v, d94g, and a90v-d94g (double mutant [dm]), present in the larger subunit of dna gyrase. in order to explicate the molecular mechanism of drug resistance corresponding to these mutations, molecular dynamics (md) and mechanics appro ...201728071975
the ppe2 protein of mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production.mycobacterium tuberculosis, the bacterium that causes tuberculosis, is one of the most successful pathogens of humans. it has evolved several adaptive skills and evasion mechanisms to hijack the immunologically educated host to suit its intracellular lifestyle. here, we show that one of the unique ppe family member proteins of m. tuberculosis, ppe2, can limit nitric oxide (no) production by inhibiting inos gene transcription. ppe2 protein has a leucine zipper dna-binding motif and a functional n ...201728071726
synthesis, identification and in vitro biological evaluation of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives.the present study describes the synthesis of two new series of 3-hydroxy-n-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives (4a-j) and 3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one derivatives (5a-7j). all the compounds were synthesized in moderate to good yield by one-pot three component cyclo-condensation reaction. the newly synthesized compounds were characterized by ft-ir, (1)h, (13)c nmr and elemental analysis. the compounds we ...201728065567
disruption of redox catalytic functions of peroxiredoxin-thioredoxin complex in mycobacterium tuberculosis h37rv using small interface binding molecules.mycobacterium tuberculosis has distinctive ability to detoxify various microbicidal superoxides and hydroperoxides via a redox catalytic cycle involving thiol reductants of peroxiredoxin (prx) and thioredoxin (trx) systems which has conferred on it resistance against oxidative killing and survivability within host. we have used computational approach to disrupt catalytic functions of prx-trx complex which can possibly render the pathogen vulnerable to oxidative killing in the host. using protein ...201728063347
dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model.cell biology differs between traditional cell culture and 3-dimensional (3-d) systems, and is modulated by the extracellular matrix. experimentation in 3-d presents challenges, especially with virulent pathogens. mycobacterium tuberculosis (mtb) kills more humans than any other infection and is characterised by a spatially organised immune response and extracellular matrix remodelling. we developed a 3-d system incorporating virulent mycobacteria, primary human blood mononuclear cells and collag ...201728063256
mycobacterium tuberculosis complex exhibits lineage-specific variations affecting protein ductility and epitope recognition.the advent of whole-genome sequencing has provided an unprecedented detail about the evolution and genetic significance of species-specific variations across the whole mycobacterium tuberculosis complex. however, little attention has been focused on understanding the functional roles of these variations in the protein coding sequences. in this work, we compare the coding sequences from 74 sequenced mycobacterial species including m. africanum, m. bovis, m. canettii, m. caprae, m. orygis, and m. ...201728062754
tuberculous scleral abscess with choroidal detachment.we present a case of ocular tuberculosis (tb) presenting as scleral abscess with choroidal detachment. a 60-year-old woman presented with intense pain, redness, watering and decreased vision in the right eye (re) for 1 week duration. slit lamp examination of re revealed diffuse scleritis with two pus-pointing areas in the supero-temporal quadrant suggesting scleral abscess. fundus examination of the re showed choroidal detachment in the temporal and inferior quadrant. left eye examination was un ...201728062426
rna expression analysis of efflux pump genes in clinical isolates of multidrug-resistant and extensively drug-resistant mycobacterium tuberculosis in south korea.tuberculosis (tb), caused by infection with mycobacterium tuberculosis, is an important communicable disease. various mechanisms of resistance to antituberculosis drugs have been reported; these are principally mutations in target genes. however, not all m. tuberculosis resistance can be explained by mutations in such genes. other resistance mechanisms associated with drug transport, such as efflux pumps, have also been reported. in this study, we investigated the expression levels of three puta ...201728062386
new tuberculosis drug leads from naturally occurring compounds.tuberculosis (tb) continues to be a significant cause of mortality and morbidity worldwide. an estimated 2 billion individuals are infected with mycobacterium tuberculosis and annually there are approximately 10 million new cases of clinical tb and 1.5 million deaths. currently available drugs and vaccines have had no significant impact on tb control. in addition, the emergence of drug resistant tb is considered a public health crisis, with some strains now resistant to all available drugs. unfo ...201728062229
hyperthermostable binding molecules on phage: assay components for point-of-care diagnostics for active tuberculosis infection.tuberculosis is the leading cause of death from infectious disease worldwide. the low sensitivity, extended processing time, and high expense of current diagnostics are major challenges to the detection and treatment of tuberculosis. mycobacterium tuberculosis ornithine transcarbamylase (mtb otc, rv1656) has been identified in the urine of patients with active tb infection and is a promising target for point-of-care diagnostics. specific binding proteins with low nanomolar affinities for mtb otc ...201728062210
molecular identification of mycobacterium tuberculosis in cattle.bovine tuberculosis continued to be a re-emerging problem in some countries especially in endemic areas due to the fact that human and animal health surveillance system is not adopted to diagnose the infection. this crisis can be attributed due to sharing of the same habitat especially in rural areas. in the present study, a total of 148 samples were collected from cattle for isolation over a period of 3 years from cattle with and without lesions, of which 67 isolates were obtained by culture. f ...201728062011
multiple cytokine responses in discriminating between active tuberculosis and latent tuberculosis infection.cytokines play an important role in cell-mediated immune responses against mycobacterium tuberculosis (mtb) infection. cytokine profile specifically associated with active tuberculosis (atb) patients, subjects with latent tuberculosis infection (ltbi) and non-infected individuals remains to be determined.201728061954
advances in basic and translational tuberculosis research: proceedings of the first meeting of report international.report international is a collaborative research network of investigators from multiple countries and institutions with the goal of establishing a bio-repository of specimens and clinical data for the study of active tb and latent tb infection (ltbi). during the first meeting of report international in boston, massachusetts, the results of research pertinent to tb control and eradication were presented, including advances in the research of mycobacterium tuberculosis (mtb) persistence and drug r ...201728061953
role and contribution of pulmonary cd103(+) dendritic cells in the adaptive immune response to mycobacterium tuberculosis.despite international control programmes, the global burden of tuberculosis remains enormous. efforts to discover novel drugs have largely focused on targeting the bacterium directly. alternatively, manipulating the host immune response may represent a valuable approach to enhance immunological clearance of the bacilli, but necessitates a deeper understanding of the immune mechanisms associated with protection against mycobacterium tuberculosis infection. here, we examined the various dendritic ...201728061951
levels of microrna mir-16 and mir-155 are altered in serum of patients with tuberculosis and associate with responses to therapy.identification of blood biomarkers that can be useful for predicting mycobacterium tuberculosis (m.tb) infection, effect of therapy and multi drug resistant (mdr) tb infected individuals is clinically useful for combating tuberculosis epidemic. in this study, we have evaluated the levels of selected mirnas in serum of tb and mdr tb patients. in addition, we have studied their levels in serum of patients post-therapy. the levels of 4-mirnas (mir-16, mir-29a, mir-125b and mir-155) were measured in ...201728061948
diagnostic yield of nontuberculous mycobacteria in patients booked for endoscopy at the university teaching hospital, lusaka.the intestinal carriage of nontuberculous mycobacteria (ntm) is associated with disease, especially in severely immunocompromised individuals. these organisms, although often considered contaminants, have been known to cause various types of illnesses. we aimed to determine the prevalence of and associated factors for ntm among patients booked for colonoscopy at the university teaching hospital (uth) in lusaka.201728061885
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
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
epidemiology of drug-resistant tuberculosis in a tertiary care center in oman, 2006-2015.the aim of this study was to estimate the prevalence and identify the risk factors for the development of drug-resistant mycobacterium tuberculosis infection in a tertiary care center in oman.201728042401
performance of xpert mtb/rif on ascitic fluid samples for detection of abdominal tuberculosis.diagnosis of abdominal tuberculosis (tb) from ascitic fluid samples using routinely available diagnostic methods is challenging due to its paucibacillary nature. although performance of xpert mtb/rif assay has been evaluated extensively on pulmonary samples, its performance on extrapulmonary samples is still under evaluation.201728042217
in silico approaches and chemical space of anti-p-type atpase compounds for discovering new antituberculous drugs.tuberculosis (tb) is one of the most important public health problems around the world. the emergence of multi-drug-resistant (mdr) and extensively drug-resistant (xdr) mycobacterium tuberculosis strains has driven the finding of alternative anti-tb targets. in this context, p-type atpases are interesting therapeutic targets due to their key role in ion homeostasis across the plasma membrane and the mycobacterial survival inside macrophages. in this review, in silico and experimental strategies ...201728111912
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
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
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
[spanish network for the study of paediatric tuberculosis. at the forefront of europe]. 201728025972
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
structural characterization and ligand/inhibitor identification provide functional insights into the mycobacterium tuberculosis cytochrome p450 cyp126a1.the mycobacterium tuberculosis h37rv genome encodes 20 cytochromes p450, including p450s crucial to infection and bacterial viability. many m. tuberculosis p450s remain uncharacterized, suggesting that their further analysis may provide new insights into m. tuberculosis metabolic processes and new targets for drug discovery. cyp126a1 is representative of a p450 family widely distributed in mycobacteria and other bacteria. here we explore the biochemical and structural properties of cyp126a1, inc ...201727932461
official american thoracic society/infectious diseases society of america/centers for disease control and prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.individuals infected with mycobacterium tuberculosis (mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [ltbi]). tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain.201727932390
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
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
risk of incident mycobacterium tuberculosis infection in patients with inflammatory bowel disease: a nationwide population-based study in south korea.the low incidence of mycobacterium tuberculosis infection and lack of adequate controls have prevented researchers from estimating tuberculosis (tb) risk in inflammatory bowel disease (ibd) patients.201727933686
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
effects of increasing the affinity of card for rna polymerase on mycobacterium tuberculosis growth, rrna transcription, and virulence.card is an essential rna polymerase (rnap) interacting protein in mycobacterium tuberculosis that stimulates formation of rnap-promoter open complexes. card plays a complex role in m. tuberculosis growth and virulence that is not fully understood. therefore, to gain further insight into the role of card in m. tuberculosis growth and virulence, we determined the effect of increasing the affinity of card for rnap. using site-directed mutagenesis guided by crystal structures of card bound to rnap, ...201727920294
divergent functions of tlr2 on hematopoietic and nonhematopoietic cells during chronic mycobacterium tuberculosis infection.we have reported that tlr2 is crucial for host resistance against chronic mycobacterium tuberculosis infection; however, which cell types are key players in this response remain unknown. this led us to decipher the relative contribution of tlr2 on nonhematopoietic and hematopoietic cells in resistance against chronic m. tuberculosis infection in mice infected with m. tuberculosis erdman. consistent with our previous report, at 8 wk of infection, tlr2 knockout (tlr2ko)→tlr2ko bone marrow chimeric ...201727920273
genotyping and prevalence of pyrazinamide- and moxifloxacin-resistant tuberculosis in china, 2000 to 2010.we investigated the prevalence, trends, and risk factors for pyrazinamide (pza) and moxifloxacin (mox) resistance among tuberculosis (tb) cases in china and also analyzed the population structure of mycobacterium tuberculosis strains. all the m. tuberculosis strains enrolled in this study were collected from the national tb prevalence surveys. each strain was genotyped by analyzing the regions of rd105 and is6110 in the ntf region. the bactec mgit 960 system was used to detect the drug susceptib ...201727919887
performance evaluation of xpert mtb/rif in a moderate tuberculosis incidence compared with taqman mtb and trcrapid m.tb.xpert mtb/rif is an automated nucleic acid amplification test (nat) that can detect the presence of mycobacterium tuberculosis complex (mtc) in clinical specimens as well as rifampicin (rif) resistance resulting from rpob mutation. despite its high sensitivity and specificity for diagnosing tuberculosis (tb) with or without rif resistance, the clinical performance of the test is variable. in this study, we evaluated the performance of xpert mtb/rif in a setting of moderate tb burden and high med ...201727919693
transmission of multidrug-resistant mycobacterium tuberculosis in shanghai, china: a retrospective observational study using whole-genome sequencing and epidemiological investigation.multidrug-resistance is a substantial threat to global elimination of tuberculosis. understanding transmission patterns is crucial for control of the disease. we used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (mdr) tuberculosis and identify potential risk factors for transmission.201727919643
insights gained from ancient biomolecules into past and present tuberculosis-a personal perspective.ancient and historical tuberculosis (tb) can be recognized by its typical paleopathology in human remains. using paleomicrobiology, it is possible to detect many more individuals infected with tb but with no visible lesions. due to advances in molecular analysis over the past two decades, it is clear that tb was widespread in humans from the neolithic period and has remained so until the present day. past human populations were associated with different lineages of the mycobacterium tuberculosis ...201727915106
antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2h-chromene and coumarin scaffold.this study reports the synthesis of new 2h-chromene or coumarin based acylhydrazones, which were evaluated for their in vitro antimycobacterial activity against reference strain mycobacterium tuberculosis h37rv and compared to the first-line antituberculosis drugs, isoniazid (inh) and ethambutol (emb). the most active compounds 7m (mic 0.13μm), 7o (mic 0.15μm) and 7k (mic 0.17μm) demonstrated antimycobacterial activity at submicromolar concentration level and remarkably minimal associated cytoto ...201727914798
maternal bcg scar is associated with increased infant proinflammatory immune responses.prenatal exposures such as infections and immunisation may influence infant responses. we had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on bcg vaccine-induced responses in ugandan infants.201727914741
new insights into the sar and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against mycobacterium tuberculosis.2-(quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of mycobacterium tuberculosis (mtb) growth. herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (mic) values against drug-susceptible and drug-resistant mycobacterium tuberculosis strains in the submicromolar range. furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they s ...201727914363
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
intestinal pneumatosis associated with tuberculosis after allogeneic hematopoietic stem cell transplantation.pneumatosis intestinalis (pi), defined as intestinal intra- and extramural gas accumulation, is a rare radiographic finding in conditions of intestinal wall damage of varied etiology. here, we report on a 56-year-old female with multiple myeloma who presented with undulating fever, fluctuating abdominal symptoms, and a distended abdomen 5 months after allogeneic hematopoietic stem cell transplantation (hsct). abdominal x-ray and ct scan documented pi with gas accumulation both in the intestinal ...201727923223
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
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
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