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identification of secretory proteins in mycobacterium tuberculosis using pseudo amino acid composition.tuberculosis is killing millions of lives every year and on the blacklist of the most appalling public health problems. recent findings suggest that secretory protein of mycobacterium tuberculosis may serve the purpose of developing specific vaccines and drugs due to their antigenicity. responding to global infectious disease, we focused on the identification of secretory proteins in mycobacterium tuberculosis. a novel method called mycosec was designed by incorporating g-gap dipeptide compositi ...201627597968
persisting positron emission tomography lesion activity and mycobacterium tuberculosis mrna after tuberculosis cure.the absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (ptb). we detected positron emission tomography and computerized tomography (pet-ct) imaging response patterns consistent with active disease, along with the presence of mycobacterium tuberculosis (mtb) mrna in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, hiv-negative patients with ptb after a s ...201627595324
the potential impact of bcg vaccine supply shortages on global paediatric tuberculosis mortality.the bacillus calmette-guérin (bcg) vaccine is provided to over 100 million neonates annually to protect against childhood tuberculosis (tb). recent bcg manufacturing interruptions highlight global supply risks. we estimated the potential impact of bcg shortfalls on global paediatric (<15 years) tb mortality.201627633883
the diagnostic accuracy of pericardial and urinary lipoarabinomannan (lam) assays in patients with suspected tuberculous pericarditis.we evaluated the diagnostic accuracy of urinary and pericardial fluid (pf) lipoarabinomannan (lam) assays in tuberculous pericarditis (tbp). from october 2009 through september 2012, 151 patients with tbp were enrolled. mycobacterium tuberculosis culture and/or pericardial histology were the reference standard for definite tbp. 49% (74/151), 33.1% (50/151) and 17.9% (27/151) of patients had definite-, probable-, and non-tb respectively; 69.5% (105/151) were hiv positive. lam elisa had the follow ...201627633798
chemical shift assignment of the intrinsically disordered n-terminus and the rubredoxin domain in the folded metal bound and unfolded oxidized state of mycobacterial protein kinase g.mycobacterium tuberculosis protein kinase g (pkng) is a 82 kda multidomain eukaryotic-like serine/threonine kinase mediating the survival of pathogenic mycobacteria within host macrophages. the n-terminal sequence preceding the catalytic kinase domain contains an approximately 75 residues long tail, which was predicted to show no regulatory secondary structure (1-75 = nors) but harbors the major in vivo phosphorylation site (t63), and a rubredoxin-like metal binding motif (74-147 = rd). in the r ...201627632081
transcriptional and physiological changes during mycobacterium tuberculosis reactivation from non-replicating persistence.mycobacterium tuberculosis can persist for years in the hostile environment of the host in a non-replicating or slowly replicating state. while active disease predominantly results from reactivation of a latent infection, the molecular mechanisms of m. tuberculosis reactivation are still poorly understood. we characterized the physiology and global transcriptomic profiles of m. tuberculosis during reactivation from hypoxia-induced non-replicating persistence. we found that m. tuberculosis reacti ...201627630619
impaired recognition of mycobacterium tuberculosis by alveolar macrophages from diabetic mice.diabetes mellitus is associated with increased tuberculosis risk and severity. we previously reported that tuberculosis susceptibility in diabetic mice results from a delay in innate immune response to inhaled mycobacterium tuberculosis, leading to delayed adaptive immune priming and, consequently, a higher plateau lung bacterial burden and greater immune pathology.201627630197
arrival of imidazo[2,1-b]thiazole-5-carboxamides: potent anti-tuberculosis agents that target qcrb.increasing interest in the potent anti-tuberculosis activity and the novel target (qcrb) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure-activity relationship studies of additional scaffolds. this study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant mycobacterium tuberculosis (mtb) as well as low toxicity to vero cell ...201627627627
ag85a dna vaccine delivery by nanoparticles: influence of the formulation characteristics on immune responses.the influence of dna vaccine formulations on immune responses in combination with adjuvants was investigated with the aim to increase cell-mediated immunity against plasmid dna (pdna) encoding mycobacterium tuberculosis antigen 85a. different ratios of pdna with cationic trimethyl chitosan (tmc) nanoparticles were characterized for their morphology and physicochemical characteristics (size, zeta potential, loading efficiency and pdna release profile) applied in vitro for cellular uptake studies ...201627626449
prediction of drug penetration in tuberculosis lesions.the penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous and drug-specific, but the factors underlying such differential partitioning are unknown. we hypothesized that drug binding to macromolecules in necrotic foci (or caseum) prevents passive drug diffusion through avascular caseum, a critical site of infection. using a caseum binding assay and maldi mass spectrometry imaging of tuberculosis drugs, we showed that binding to caseum inversely correlates with passive diffu ...201627626295
diphenylether-modified 1,2-diamines with improved drug properties for development against mycobacterium tuberculosis.new treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant mycobacterium tuberculosis (mtb). we report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as tbl-140, which has a minimal inhibitory concentration (mic99) of 1.2 μg/ml. tbl-140 is effective against drug-resistant mtb and nonreplicating bacteria. in addition, tbl-140 eliminates expansion of mtb in cell culture infection assays at its ...201627626102
rational engineering of a virulence gene from mycobacterium tuberculosis facilitates proteomic analysis of a natural protein n-terminus.mass spectrometry (ms) for the detection of proteins is an indispensable tool for evaluating the biological processes of the proteome. proteomics frequently requires proteolysis of proteins into peptide fragments. proteins can be refractory to ideal proteolysis at the sequence level rendering them difficult to analyze by routine proteomics methods. esxa (esat-6, early secreted antigen, 6kda) is a major virulence determinant of mycobacterium tuberculosis, the cause of human tuberculosis. esxa is ...201627625110
loss of a class a penicillin-binding protein alters β-lactam susceptibilities in mycobacterium tuberculosis.recent studies have renewed interest in β-lactam antibiotics as a potential treatment for mycobacterium tuberculosis infection. to explore the opportunities and limitations of this approach, we sought to better understand potential resistance mechanisms to β-lactam antibiotics in m. tuberculosis. we identified mutations in the penicillin-binding protein (pbp) pona2 that were able to confer some degree of resistance to the cephalosporin subclass of β-lactams. surprisingly, deletion of pona2 also ...201627624961
discovery of allosteric and selective inhibitors of inorganic pyrophosphatase from mycobacterium tuberculosis.inorganic pyrophosphatase (ppiase) is an essential enzyme that hydrolyzes inorganic pyrophosphate (ppi), driving numerous metabolic processes. we report a discovery of an allosteric inhibitor (2,4-bis(aziridin-1-yl)-6-(1-phenylpyrrol-2-yl)-s-triazine) of bacterial ppiases. analogues of this lead compound were synthesized to target specifically mycobacterium tuberculosis (mtb) ppiase (mtppiase). the best analogue (compound 16) with a ki of 11 μm for mtppiase is a species-specific inhibitor. cryst ...201627622287
mycobacterium tuberculosis zinc metalloprotease-1 assists mycobacterial dissemination in zebrafish.zinc metalloprotease-1 (zmp1) from mycobacterium tuberculosis (m.tb), the tuberculosis (tb) causing bacillus, is a virulence factor involved in inflammasome inactivation and phagosome maturation arrest. we earlier reported that zmp1 was secreted under granuloma-like stress conditions, induced th2 cytokine microenvironment and was highly immunogenic in tb patients as evident from high anti-zmp1 antibody titers in their sera. in this study, we deciphered a new physiological role of zmp1 in mycobac ...201627621726
executive summary: official american thoracic society/centers for disease control and prevention/infectious diseases society of america clinical practice guidelines: treatment of drug-susceptible tuberculosis.the american thoracic society, centers for disease control and prevention, and infectious diseases society of america jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the european respiratory society and the us national tuberculosis controllers association. representatives from the american academy of pediatrics, the canadian thoracic society, the international union against tuberculosis and lung disease, and the wo ...201627621353
delamanid susceptibility testing of mycobacterium tuberculosis using the resazurin microtitre assay and the bactec™ mgit™ 960 system-authors' response. 201627621178
bioinformatics identification of drug resistance-associated gene pairs in mycobacterium tuberculosis.tuberculosis is a chronic infectious disease caused by mycobacterium tuberculosis (mtb). due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. some single mutations have been identified to be significantly linked with drug resistance. however, the prior research did not take gene-gene interactions into account, and the eme ...201627618895
stereocontrolled total synthesis of muraymycin d1 having a dual mode of action against mycobacterium tuberculosis.a stereocontrolled first total synthesis of muraymycin d1 (1) has been achieved. the synthetic route is highly stereoselective, featuring (1) selective β-ribosylation of the c2-methylated amino ribose, (2) selective strecker reaction, and (3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (epi-capreomycidine). the acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with th ...201627617631
mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination.the mechanisms by which the airborne pathogen mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (tb) in humans, remains poorly understood. herein, we used a transcriptomic approach to investigate the host cell gene expression profile in m. tuberculosis-infected human macrophages (μφ). we identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significan ...201627616470
tracing mycobacterium tuberculosis transmission by whole genome sequencing in a high incidence setting: a retrospective population-based study in east greenland.in east greenland, a dramatic increase of tuberculosis (tb) incidence has been observed in recent years. classical genotyping suggests a genetically similar mycobacterium tuberculosis (mtb) strain population as cause, however, precise transmission patterns are unclear. we performed whole genome sequencing (wgs) of mtb isolates from 98% of culture-positive tb cases through 21 years (n = 182) which revealed four genomic clusters of the euro-american lineage (mainly sub-lineage 4.8 (n = 134)). the ...201627615360
elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents.we report the design and synthesis of a series of non-nucleoside mtbtmpk inhibitors (1-14) based on the gram-positive bacterial tmpk inhibitor hit compound 1. a practical synthesis was developed to access these analogues. several compounds show promising mtbtmpk inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization.201627614917
anti-inflammatory, antioxidant and anti-mycobacterium tuberculosis activity of viridiflorol: the major constituent of allophylus edulis (a. st.-hil., a. juss. & cambess.) radlk.the leaves of allophylus edulis (a. st.-hil., a. juss. & cambess.) radlk. (sapindaceae) are traditionally used as a natural anti-inflammatory agent; however, there are no scientific studies demonstrating its activity essential oil. the content of essential oil in a. edulis may be the chemical basis to explain its ethnobotanical uses, since infusions of this plant are used to treat inflammation in the traditional medicine in brazil.201627612433
overview on mechanisms of isoniazid action and resistance in mycobacterium tuberculosis.isoniazid (inh) is one of the most active compounds used to treat tuberculosis (tb) worldwide. in addition, inh has been used as a prophylactic drug for individuals with latent mycobacterium tuberculosis (mtb) infection to prevent reactivation of disease. importantly, the definition of multidrug resistance (mdr) in tb is based on the resistance of mtb strains to inh and rifampicin (rif). despite its simple chemical structure, the mechanism of action of inh is very complex and involves several di ...201627612406
tuberculosis tenosynovitis with multiple rice bodies of the flexor tendons in the wrist: a case report.one of the infectious causes of wrist tenosynovitis is mycobacterium tuberculosis. tendon sheath involvement is rare. herein, we report the diagnosis and treatment of a patient with neglected wrist flexor tendon sheath tuberculosis.201627611797
[sapm-induced fusion blocking of autophagosome-lysosome is depended on interaction with rab7].objective to study the role of rab7 in the blockage of autophagosome-lysosome fusion induced by secretory acid phosphatase (sapm), a virulence factor of mycobacterium tuberculosis. methods the raw264.7 cells were transfected with sirab7, and the p62 was detected using western blotting. after transfected with mcherry-sapm, the co-localization of sapm and rab7 in raw264.7 cells was detected by immunofluorescence cytochemistry and the interaction of sapm with rab7 was determined by co-immunoprecipi ...201627609571
exploring intein inhibition by platinum compounds as an antimicrobial strategy.inteins, self-splicing protein elements, interrupt genes and proteins in many microbes, including the human pathogen mycobacterium tuberculosis using conserved catalytic nucleophiles at their n- and c-terminal splice junctions, inteins are able to excise out of precursor polypeptides. the splicing of the intein in the mycobacterial recombinase reca is specifically inhibited by the widely used cancer therapeutic cisplatin, cis-[pt(nh3)2cl2], and this compound inhibits mycobacterial growth. mass s ...201627609519
the mimic epitopes of mycobacterium tuberculosis screened by phage display peptide library have serodiagnostic potential for tuberculosis.mycobacterium tuberculosis is an obligate pathogenic bacterial species in the family of mycobacteriaceae and attracts excessive immune responses which cause pathology of the lungs in active tuberculosis. the lack of more sensitive and effective diagnosis reagents advocates a further recognition for the fast diagnostic and immunological measures for tuberculosis. here, two 12-mer peptides with core sequences of svsvgmkpsprp (cs1) and tmgftaprfphy (cs2) were screened from a phage display random pe ...201627609463
microbiome changes during tuberculosis and antituberculous therapy.the critical role of commensal microbiota in the human body has been increasingly recognized, and our understanding of its implications in human health and disease has expanded rapidly. the lower respiratory tract contains diverse communities of microbes known as lung microbiota, which are present in healthy individuals and in individuals with respiratory diseases. the dysbiosis of the airway microbiota in pulmonary tuberculosis (tb) may play a role in the pathophysiological processes associated ...201627608937
oxygen availability and metabolic dynamics during mycobacterium tuberculosis latency.in vitro models of mycobacterium tuberculosis (mtb) nonreplicating persistence (nrp) suggest the rate of oxygen ( o2 ) depletion is a significant determinant in persistence. however, few studies have characterized the metabolic association between slow and rapid o2 depletion rates and successful versus failed persistence.201627608448
[hemophagocytic syndrome associated with tuberculosis in a patient with acquired immunodeficiency].the secondary hemophagocytic syndrome is rare in children and even rarer associated with tuberculosis. e report the case of a patient with acquired immunodeficiency syndrome, disseminated tuberculosis and hemophagocytic syndrome. an 8-year-old girl, diagnosed with acquired immunodeficiency syndrome, was admitted due to fever, vomiting and abdominal pain. she presented abdominal distension, dehydration, tachypnea, crackles and wheezing in both lungs, anemia, thrombocytopenia and coagulopathy. she ...201627606663
in vivo mycobacterium tuberculosis fluoroquinolone resistance emergence: a complex phenomenon poorly detected by current diagnostic tests.heteroresistance, described both in terms of various point mutations resulting in different levels of resistance and in terms of a mixture of mutant and wt bacilli, is identified in up to one-third of fluoroquinolone (fq)-resistant mycobacterium tuberculosis isolates. heteroresistance is a challenge for current phenotypic and genotypic susceptibility testing (dst) regimes. we aimed to compare the performances of different phenotypic and genotypic dst in the context of fq heteroresistance by mimi ...201627605600
genotype(®) mtbdrsl assay for resistance to second-line anti-tuberculosis drugs.genotype® mtbdrsl (mtbdrsl) is a rapid dna-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (slids) in mycobacterium tuberculosis complex. mtbdrsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. the test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. version 1.0 requires a smear-positive specime ...201627605387
controlling inflammation: a superior way to control tb. 201627605065
peroxiredoxin 1 contributes to host defenses against mycobacterium tuberculosis.peroxiredoxin (prdx)1 is an antioxidant that detoxifies hydrogen peroxide and peroxinitrite. compared with wild-type (wt) mice, prdx1-deficient (prdx1(-/-)) mice showed increased susceptibility to mycobacterium tuberculosis and lower levels of ifn-γ and ifn-γ-producing cd4(+) t cells in the lungs after m. tuberculosis infection. il-12 production, c-rel induction, and p38 mapk activation levels were lower in prdx1(-/-) than in wt bone marrow-derived macrophages (bmdms). ifn-γ-activated prdx1(-/-) ...201627605010
tb or not tb? improving the understanding and diagnosis of tuberculosis through metabolomics. 201627643758
added value of ip-10 as a read-out of mycobacterium tuberculosis: specific immunity in young children.we have explored the added value of interferon-γ (ifnγ)-inducible protein 10 as a read-out of mycobacterium tuberculosis-specific immunity in young indian children, where the sensitivity of the ifnγ release assays for tuberculosis is poor. reduced frequency of indeterminate results and an increased sensitivity for tuberculosis suggest a potential for fewer missed cases with a combined ifnγ/inducible protein 10 read-out in a 4th generation ifnγ release assays.201627642776
a target-based whole cell screen approach to identify potential inhibitors of mycobacterium tuberculosis signal peptidase.the general secretion (sec) pathway is a conserved essential pathway in bacteria and is the primary route of protein export across the cytoplasmic membrane. during protein export, the signal peptidase lepb catalyzes the cleavage of the signal peptide and subsequent release of mature proteins into the extracellular space. we developed a target-based whole cell assay to screen for potential inhibitors of lepb, the sole signal peptidase in mycobacterium tuberculosis, using a strain engineered to un ...201627642770
[comparison of the characteristics of expanded cells in human pbmcs activated by combination of mtb-ag and il-15 or il-2 in vitro].objective to investigate the biological characteristics of expanded cells in human peripheral blood mononuclear cells (pbmcs) activated by the combination of mycobacterium tuberculosis antigen (mtb-ag) and il-15 or il-2 in vitro. methods fresh pbmcs of normal subjects were stimulated with mtb-ag and il-15 or mtb-ag and il-2 for 12 days. proportions of γ δ t cells, natural killer (nk) cells and cd4(+) t cells in the expanded cells were analyzed by flow cytometry; the numbers of the three lymphocy ...201627667452
new and old hot drug targets in tuberculosis.tuberculosis is an infectious disease caused by the bacillus mycobacterium tuberculosis. the world health organization publishes global tuberculosis reports annually in order to provide the latest information in the surveillance of drug resistance. given the alarming rise of resistance to antitubercular drugs worldwide, finding new cellular targets and developing new analogues or new compounds with greater potency against already known targets are both important aspects in fighting drug-sensitiv ...201627666933
[surgical treated spondylodiscitis epidemiological study].the term spondylodiscitis aims to describe any spinal infection. medical treatment is the gold standard; nevertheless, surgical treatment can be indicated. the aim of this work was to study the epidemiological profile in a group of patients with spondylodiscitis surgically treated in the same medical institution between 1997 and 2013.201627649016
acute and fatal isoniazid-induced hepatotoxicity: a case report and review of the literature.this paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. a 65-year-old female diagnosed with latent mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. she was admitted to the hospital for epigastric and right sided flank pain of one-week duration. laboratory results and imaging confirmed hepatitis. after ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (pr ...201627648319
a second, druggable binding site in udp-galactopyranose mutase from mycobacterium tuberculosis?udp-galactopyranose mutase (ugm), a key enzyme in the biosynthesis of mycobacterial cell walls, is a potential target for the treatment of tuberculosis. in this work, we investigate binding models of a non-substrate-like inhibitor, ms-208, with m. tuberculosis ugm. initial saturation transfer difference (std) nmr experiments indicated a lack of direct competition between ms-208 and the enzyme substrate, and subsequent kinetic assays showed mixed inhibition. we thus hypothesized that ms-208 binds ...201627653508
tuberculosis susceptibility and vaccine protection are independently controlled by host genotype.the outcome of mycobacterium tuberculosis infection and the immunological response to the bacillus calmette-guerin (bcg) vaccine are highly variable in humans. deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of bcg has proven difficult in natural populations. we developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genet ...201627651361
sliding clamp of dna polymerase iii as a drug target for tb therapy: comprehensive conformational and binding analysis from molecular dynamic simulations.tuberculosis, caused by mycobacterium tuberculosis, is one of the most common causes of death in the world. mycobacterium tuberculosis -sliding clamp is a protein essential for many important dna transactions including replication and dna repair proteins, thus, a potential drug target for tuberculosis. further investigation is needed in understanding dna polymerase sliding clamp structure, especially from a computational perspective. in this study, we employ a wide-range of comparative molecular ...201627651172
evaluation of isothermal target and probe amplification (itpa) for the detection of mycobacterium tuberculosis.this study compared the diagnostic power of isothermal target and probe amplification (itpa) with the existing real-time pcr for the detection of mycobacterium tuberculosis (mtb).201627650621
a multilaboratory, multicountry study to determine mic quality control ranges for phenotypic drug susceptibility testing of selected first-line antituberculosis drugs, second-line injectables, fluoroquinolones, clofazimine, and linezolid.our objective was to establish reference mic quality control (qc) ranges for drug susceptibility testing of antimycobacterials, including first-line agents, second-line injectables, fluoroquinolones, and world health organization category 5 drugs for multidrug-resistant tuberculosis using a 7h9 broth microdilution mic method. a tier-2 reproducibility study was conducted in eight participating laboratories using clinical laboratory and standards institute (clsi) guidelines. three lots of custom-m ...201627654338
a multilaboratory, multicountry study to determine bedaquiline mic quality control ranges for phenotypic drug susceptibility testing.the aim of this study was to establish standardized drug susceptibility testing (dst) methodologies and reference mic quality control (qc) ranges for bedaquiline, a diarylquinoline antimycobacterial, used in the treatment of adults with multidrug-resistant tuberculosis. two tier-2 qc reproducibility studies of bedaquiline dst were conducted in eight laboratories using clinical laboratory and standards institute (clsi) guidelines. agar dilution and broth microdilution methods were evaluated. myco ...201627654337
human leukocyte antigen class 1 genotype distribution and analysis in persons with active tuberculosis and household contacts from central uganda.to determine the distribution of human leukocyte antigen (hla) class i genotypes in a ugandan population of persons with tuberculosis (tb) and establish the relationship between class i hla types and mycobacterium tuberculosis (mtb) disease.201627659198
[comparative genomic analysis of peruvian strains of mycobacterium tuberculosis].to comparatively analyze three genomic sequences of mycobacterium tuberculosis(mtb), including sensitive (ins-sen), multi-drug-resistant (ins-mdr), and extremely drug-resistant (ins-xdr) strains, collected in lima, peru.201627656924
bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis.the developing countries are having an abruptly growing number of drug resistant tuberculosis cases. multidrug-resistant tuberculosis (mdr-tb) is a type of tb in which the strain of mycobacterium tuberculosis is resistant to at least isoniazid and rifampicin, the two most effective of the four first-line tb drugs (the other two drugs being ethambutol and pyrazinamide). the management of such cases is complex and requires a treatment for 24-27 months. the current guidelines available for the mana ...201627656462
identification potential biomarkers in pulmonary tuberculosis and latent infection based on bioinformatics analysis.the study aimed to identify the potential biomarkers in pulmonary tuberculosis (tb) and tb latent infection based on bioinformatics analysis.201627655333
chronic lung disease in hiv-infected children established on antiretroviral therapy.respiratory disease is a major cause of morbidity and mortality in hiv-infected children. despite antiretroviral therapy (art), children suffer chronic symptoms. we investigated symptom prevalence, lung function and exercise capacity among older children established on art and an age-matched hiv-uninfected group.201627662546
lipase processing of complex lipid antigens.mycobacterium tuberculosis synthesizes a wide variety of complex lipids that can serve as antigens in immune recognition of the bacterium. in this issue of cell chemical biology, gilleron et al. (2016) identify key enzymes essential for lipid antigen processing, which is required for cd1b-restricted t cell activation.201627662250
preventing transmission of mycobacterium tuberculosis in health care settings.patients with tuberculosis (tb) pose a risk to other patients and health care workers, and outbreaks in health care settings occur when appropriate infection control measures are not used. in this article, we discuss strategies to prevent transmission of mycobacterium tuberculosis within health care settings. all health care facilities should have an operational tb infection control plan that emphasizes the use of a hierarchy of controls (administrative, environmental, and personal respiratory p ...201627660092
esx secretion systems: mycobacterial evolution to counter host immunity.mycobacterium tuberculosis uses sophisticated secretion systems, named 6 kda early secretory antigenic target (esat6) protein family secretion (esx) systems (also known as type vii secretion systems), to export a set of effector proteins that helps the pathogen to resist or evade the host immune response. since the discovery of the esx loci during the m. tuberculosis h37rv genome project, structural biology, cell biology and evolutionary analyses have advanced our knowledge of the function of th ...201627665717
efficacious in vitro and in vivo effects of dihydrosphingosine-ethambutol analogues against susceptible and multi-drug-resistant mycobacterium tuberculosis.tuberculosis (tb) is a major worldwide health problem in part due to the lack of new drugs and the emergence of multidrug-resistant strains (mdr). the aim of this study was to select anti-tuberculosis drug candidates from a collection of 69 synthetic sphingosine-ethambutol analogues through in vitro and in vivo evaluations.201627664485
long-term storage at -80°c: effect on rate of recovery of mycobacterium tuberculosis from direct acid-fast bacilli smear-positive sputum samples.the aim of this study was to evaluate the difference in the rate of recovery of mycobacterium tuberculosis (mtb) from routinely cultured sputum and long-term stored sputum specimens (at -80°c) using löwenstein-jensen (lj) media, mycobacterium growth indicator tube (bbl mgit(tm) ), and middlebrook 7h11 (mb 7h11) agar.201627685316
protective efficacy and pulmonary immune response following subcutaneous and intranasal bcg administration in mice.despite global coverage of intradermal bcg vaccination, tuberculosis remains one of the most prevalent infectious diseases in the world. preclinical data have encouraged pulmonary tuberculosis vaccines as a promising strategy to prevent pulmonary disease, which is responsible for transmission. in this work, we describe the methodology used to demonstrate in the mouse model the benefits of intranasal bcg vaccination when compared to subcutaneous. our data revealed greater protective efficacy foll ...201627684521
kinetic and mutational studies of the adenosine diphosphate ribose hydrolase from mycobacterium tuberculosis.mycobacterium tuberculosis represents one of the world's most devastating infectious agents - with one third of the world's population infected and 1.5 million people dying each year from this deadly pathogen. as part of an effort to identify targets for therapeutic intervention, we carried out the kinetic characterization of the product of gene rv1700 of m. tuberculosis. based on its sequence and its structure, the protein had been tentatively identified as a pyrophosphohydrolase specific for a ...201627683242
urgent implementation in a hospital setting of a strategy to rule out secondary cases caused by imported extensively drug-resistant mycobacterium tuberculosis strains at diagnosis.current migratory movements require new strategies for rapidly tracking the transmission of high-risk imported mycobacterium tuberculosis strains. whole-genome sequencing (wgs) enables us to identify single-nucleotide polymorphisms (snps) and therefore design pcrs to track specific relevant strains. however, fast implementation of these strategies in the hospital setting is difficult because professionals working in diagnostics, molecular epidemiology, and genomics are generally at separate inst ...201627682128
mir-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to mycobacterium tuberculosis.the regulation of host-pathogen interactions during mycobacterium tuberculosis (mtb) infection remains unresolved. micrornas (mirnas) are important regulators of the immune system, and so we used a systems biology approach to construct an mirna regulatory network activated in macrophages during mtb infection. our network comprises 77 putative mirnas that are associated with temporal gene expression signatures in macrophages early after mtb infection. in this study, we demonstrate a dual role for ...201627681624
evolutionary history and ongoing transmission of phylogenetic sublineages of mycobacterium tuberculosis beijing genotype in china.mycobacterium tuberculosis beijing genotype originated in china and has undergone a dramatic population growth and global spread in the last century. here, a collection of m. tuberculosis beijing family isolates from different provinces across all china was genotyped by high-resolution (24-miru-vntr) and low-resolution, high-rank (modern and ancient sublineages) markers. the molecular profiles and global and local phylogenies were compared to the strain phenotype and patient data. the phylogeogr ...201627681182
chevalone c analogues and globoscinic acid derivatives from the fungus neosartorya spinosa kku-1nk1.four meroterpenoids, 1-hydroxychevalone c, 1-acetoxychevalone c, 1,11-dihydroxychevalone c, and 11-hydroxychevalone c and two ester epimers, 2s,4s-spinosate and 2s,4r-spinosate, together with seven known compounds, chevalones b, c, and e, tryptoquivaline, nortryptoquivaline, tryptoquivaline l, and quinadoline a were isolated from the fungus neosartorya spinosa. their structures were established based on spectroscopic data analyses. the theoretical ecd spectra of epimers, 2s,4s-spinosate and 2s,4 ...201627680770
large retropharyngeal abscesses in an immunocompetent adult patient with disseminated tuberculosis.background the retropharyngeal abscess is a rare presentation of head and neck tuberculosis. the pathogenesis of the abscess formation in the retropharyngeal space in the adult is controversial. case report we report a case of large retropharyngeal abscesses in a 46-year-old man with disseminated tuberculosis. the patient had severe progressive dysphagia, weight loss, and a slowly enlarging bilateral cervical mass during a period of three months. his posterior pharynx wall was bulging and red, a ...201627680292
repurposing clinically approved cephalosporins for tuberculosis therapy.while modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (tb) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. common chemical patterns required for activity against mycobacterium tuberculosis were identified using structure-activity relationships (sar) studies. numerous cephalosporins were synergistic with rifampicin, the ...201627678056
discovery and biophysical evaluation of first low nanomolar hits targeting cyp125 of m. tuberculosis.tuberculosis, which is predominantly caused by mycobacterium tuberculosis (mtb), is still the most lethal bacterial infection with 1.5 million casualties in 2014. moreover, the fact that the appearance of resistant mutants and long-term treatment are coupled with economic problems in developing countries hampers an efficient therapy. interference with the essential cholesterol metabolism of mtb could be a promising novel strategy to fight mtb infections. cyp125, a p450 enzyme in mtb, has been sh ...201627677638
development and evaluation of an in-house single step loop-mediated isothermal amplification (ss-lamp) assay for the detection of mycobacterium tuberculosis complex in sputum samples from moroccan patients.tuberculosis (tb) is a major global health problem and remains the leading cause of morbidity and mortality in developing countries. routinely used tb diagnostic methods, in most endemic areas, are time-consuming, often less-sensitive, expensive and inaccessible to most patients. therefore, there is an urgent need for the development of early, easy to use and effective diagnosis tools of tb, which can be effectively integrated into resource limited settings, to anticipate the early treatment and ...201627677540
duplex detection of the mycobacterium tuberculosis complex and medically important non-tuberculosis mycobacteria by real-time pcr based on the rnpb gene.a duplex real-time pcr based on the rnpb gene was developed for mycobacterium spp. the assay was specific for the mycobacterium tuberculosis complex (mtb) and also detected all 19 tested species of non-tuberculous mycobacteria (ntm). the assay was evaluated on 404 clinical samples: 290 respiratory samples and 114 from tissue and other non-respiratory body sites. m. tuberculosis was detected by culture in 40 samples and in 30 samples by the assay. the mtb assay showed a sensitivity similar to roc ...201627677426
validation of coabc as a bactericidal target in the coenzyme a pathway of mycobacterium tuberculosis.mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme a to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. as such, the essential pantothenate and coenzyme a biosynthesis pathways have attracted attention as targets for tuberculosis drug development. to identify the optimal step for coenzyme a pathway disruption in m. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme a pathway g ...201627676316
structure-activity relationships of the mepicides: n-acyl and o-linked analogs of fr900098 as inhibitors of dxr from mycobacterium tuberculosis and yersinia pestis.despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. the methylerythritol phosphate (mep) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. we and others have explored inhibitors of the mep pathway as novel antibacterial agents. mycobacterium tuberculosis, the ...201627676224
dataset generated using hyperplexing and click chemistry to monitor temporal dynamics of newly synthesized macrophage secretome post infection by mycobacterial strains.here we provide data for silac and itraq based hyperplexing combined with boncat based click chemistry for selective enrichment of newly synthesized proteins secreted by thp1 macrophages at various time points after infection with four different strains of mycobacterium tuberculosis. the macrophages were infected with h37ra, h37rv, bnd433 and jal2287 strains of m. tuberculosis. newly-synthesized secreted host proteins were observed, starting from six hours post-infection till 26 h, at 4 h interv ...201627672675
inhibiting mycobacterium tuberculosis within and without.tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of mycobacterium tuberculosis intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in c ...201627672155
the incidence of tuberculosis transmission among family members and outside households.the risk of mycobacterium tuberculosis complex (mtbc) infection is correlated with the concentration of infectious particles and exposure time. in closed populations, healthy people staying in very frequent, close and prolonged contact with a smear-positive person, become infected and represent another link in the chain of transmission of the disease. therefore, in the fight against tuberculosis, an important element is quick identification of the patient and potentially infected people from his ...201627672069
mycobacterium tuberculosis arylamine n-acetyltransferase acetylates and thus inactivates para-aminosalicylic acid.mycobacterium tuberculosis arylamine n-acetyltransferase (tbnat) is able to acetylate para-aminosalicylic acid (pas) both in vitro and in vivo as determined by high-performance liquid chromatography (hplc) and electrospray ionization-mass spectrometry (esi-ms) techniques. the antituberculosis activity of the acetylated pas is significantly reduced. as a result, overexpression of tbnat in m. tuberculosis results in pas resistance, as determined by mic tests and drug exposure experiments. taken to ...201627671064
association between embb codon 306 mutations, phenotypic resistance profiles, and genotypic characterization in clinical mycobacterium tuberculosis isolates from hebei, china.ethambutol (emb) is an essential first-line drug for tuberculosis (tb) treatment. nucleotide substitutions at embb codon 306 (embb306) have been proposed to be a potential marker for emb resistance and a predictor of broad drug resistance in clinical mycobacterium tuberculosis isolates. however, discordant findings about the association between embb306 mutations and emb resistance were reported. hebei province is located in the beijing-tianjin-hebei integration region in china; however, little i ...201627671062
persistently high prevalence of primary resistance and multidrug resistance of tuberculosis in heilongjiang province, china.the spread of multidrug-resistant tuberculosis (mdr-tb) mycobacterium tuberculosis (m. tuberculosis) strains has been a big challenge to the tb control and prevention in china. knowledge about patterns of drug resistance in tb high-burden areas of china is crucial to develop appropriate control strategies. we conducted a comprehensive investigation of the resistance pattern of m. tuberculosis in heilongjiang province.201627670780
latent tuberculosis infection (ltbi): a real host defence or a permanent threat?screening of latent infection by mycobacterium tuberculosis (ltbi) and treatment of positive subjects is the key point in the prevention of tb; such a strategy should be performed mainly among individuals with risk of progression. progression from ltbi to active tb is highest both in recent contacts of patients with active tb, and in immunocompromised subjects. therefore, ltbi could either be considered a permanent host defence or, seen from the opposite point of view, it could represent a long- ...201627668896
proteomics analysis of three different strains of mycobacterium tuberculosis under in vitro hypoxia and evaluation of hypoxia associated antigen's specific memory t cells in healthy household contacts.in vitro mimicking conditions are thought to reflect the environment experienced by mycobacterium tuberculosis inside the host granuloma. the majority of in vitro dormancy experimental models use laboratory-adapted strains h37rv or erdman instead of prevalent clinical strains involved during disease outbreaks. thus, we included the most prevalent clinical strains (s7 and s10) of m. tuberculosis from south india in addition to h37rv for our in vitro oxygen depletion (hypoxia) experimental model. ...201627667981
a functional role for antibodies in tuberculosis.while a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. in many infectious diseases, antibodies (abs) are powerful biomarkers and important immune mediators. however, in mycobacterium tuberculosis (mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. using an unbiased antibody profiling approach, we show that individuals with late ...201627667685
anti-tubercular activities of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues endowed with high activity toward non-replicative mycobacterium tuberculosis.thirty three derivatives of 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues were synthesized by molecular modification of a reported antimycobacterial molecule (gsk163574a). compounds were evaluated in vitro against actively replicative and nutrient starved non-replicative mycobacterium tuberculosis (mtb), enzymatic screening and cytotoxicity against raw 264.7 cell line. among the compounds, 2-ethyl-n-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin ...201627667550
childhood tuberculosis: a descriptive study in a pneumo-pediatrics department in tunisia.objective to assess the different localizations of tuberculosis (tb) in children in a pneumopediatric department in tunisia and to describe its diagnosis tools since clinical investigations of childhood tb are challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. methods forty-six cases of tb in children were studied between 2008 and 2013. clinical history, examination and chest radiography were reported. several investigations have been conducted to ...201627704508
clinical impact on tuberculosis treatment outcomes of discordance between molecular and growth-based assays for rifampin resistance, california 2003-2013.background.  data from international settings suggest that isolates of mycobacterium tuberculosis with rpob mutations testing phenotypically susceptible to rifampin (rif) may have clinical significance. we analyzed treatment outcomes of california patients with discordant molecular-phenotypic rif results. methods.  we included tuberculosis (tb) patients, during 2003-2013, whose specimens tested rif susceptible phenotypically but had a rpob mutation determined by pyrosequencing. demographic data ...201627704008
induction of an immune-protective t-cell repertoire with diverse genetic coverage by a novel viral-vectored tuberculosis vaccine in humans.whether a candidate tuberculosis vaccine induces clinically relevant protective t-cell repertoires in humans will not be known until the completion of costly efficacy clinical trials.201627703038
re-initiation of biologics after the development of tuberculosis under anti-tnf therapy.the use of anti-tnf agents is associated with an increased risk of tuberculosis (tb) and anti-tnf agents are stopped when active tb develops. however, discontinuation of treatment can result in flare of the underlying disease. the charts of 22 patients who developed active tb among a cohort of 2754 patients using anti-tnf agents between 2001 and 2013 were reviewed retrospectively. patients restarting biologics during further follow-up were identified. one patient with miliary tb died within 1 mo ...201627699578
nonmutational compensation of the fitness cost of antibiotic resistance in mycobacteria by overexpression of tlya rrna methylase.several studies over the last few decades have shown that antibiotic resistance mechanisms frequently confer a fitness cost and that these costs can be genetically ameliorated by intra- or extragenic second-site mutations, often without loss of resistance. another, much less studied potential mechanism by which the fitness cost of antibiotic resistance could be reduced is via a regulatory response where the deleterious effect of the resistance mechanism is lowered by a physiological alteration t ...201627698071
tuberculosis in hemodialysis.chronic uremia puts patients at increased risk of infectious complications, in particular, tuberculosis. in this prospective study, we analyzed the clinical, paraclinical, and therapeutic features as well as outcome for all patients on chronic hemodialysis with tuberculosis from january 2010 through august 2012. sixty-one patients were admitted for bacterial infections, 23% of them for tuberculosis. fever was present in 71% of cases, and crp elevated in all cases. the tuberculin skin test was po ...201627694081
trims and galectins globally cooperate and trim16 and galectin-3 co-direct autophagy in endomembrane damage homeostasis.selective autophagy performs an array of tasks to maintain intracellular homeostasis, sterility, and organellar and cellular functionality. the fidelity of these processes depends on precise target recognition and limited activation of the autophagy apparatus in a localized fashion. here we describe cooperation in such processes between the trim family and galectin family of proteins. trims, which are e3 ubiquitin ligases, displayed propensity to associate with galectins. one specific trim, trim ...201627693506
isoniazid and rifampin pharmacokinetics in two asian elephants (elephas maximus) infected with mycobacterium tuberculosis.this report describes the pharmacokinetic profiles of chronically administered oral isoniazid and rifampin in one adult male and one adult female asian elephant ( elephas maximus ) that were asymptomatically infected with mycobacterium tuberculosis . rifampin's half-life was reduced when compared to previous single-dose pharmacokinetic profiles of healthy uninfected asian elephants. both elephants experienced delayed absorption of isoniazid and rifampin as compared to previous pharmacokinetic st ...201627691967
small-molecule probes reveal esterases with persistent activity in dormant and reactivating mycobacterium tuberculosis.mycobacterium tuberculosis (mtb) is the deadliest bacterial pathogen in the world. an estimated one-third of humans harbor mtb in a dormant state. these asymptomatic, latent infections impede tuberculosis eradication due to the long-term potential for reactivation. dormant mtb has reduced enzymatic activity, but hydrolases that remain active facilitate pathogen survival. we targeted mtb esterases, a diverse set of enzymes in the serine hydrolase family, and studied their activities using both ac ...201627690385
fluorescent quantitative pcr detection of mycobacterium tuberculosis in tissue sections from granulomatous lesions retrieved using edta.this study aimed to use edta to retrieve paraffin-embedded tissue sections of inflammatory granulomatous lesions and increase the detection rate of tuberculosis (tb)/non-tuberculous mycobacteria. due to the influence of chemical reagents during the fixation process, the amplification of fluorescent quantitative pcr was blocked after dna extraction, and the results were not ideal.201627687825
benzimidazole-core as an antimycobacterial agent.mycobacterium tuberculosis (mtb) is considered as one of the precarious bacterial infections around the world. through a projected 8.7 million new tuberculosis (tb) cases and 1.4 million mortalities per annum, this deadly infection resulted insubstantial amount of human deaths than any other single organism bacterial infections. tb is one of india's most threatening human health problems and it accounts for approximately 33% of the global health issues. subsequently, for tb there is an imperativ ...201627686965
mass spectrometry applied to the identification of mycobacterium tuberculosis and biomarker discovery.an adequate and effective tuberculosis (tb) diagnosis system has been identified by the world health organization as a priority in the fight against this disease. over the years, several methods have been developed to identify the bacillus, but bacterial culture remains one of the most affordable methods for most countries. for rapid and accurate identification, however, it is more feasible to implement molecular techniques, taking advantage of the availability of public databases containing pro ...201627718305
role of il-10 and tnf-α during mycobacterium tuberculosis infection in murine alveolar macrophages.mycobacterium tuberculosis (mtb) is known to be responsible for tuberculosis (tb), but the pathogenesis of this disease and the host defense mechanisms involved are, for the most part, poorly understood. in this study, we divided 30 male c57bl/6 mice into control and infection groups, and following injection with physiological saline or mtb, respectively, euthanized five mice from each group on days 1, 3, and 7. tnf-α and il-10 levels were measured by enzyme-linked immunosorbent assay and flow c ...201627706765
the transcriptional signature of active tuberculosis reflects symptom status in extra-pulmonary and pulmonary tuberculosis.mycobacterium tuberculosis infection is a leading cause of infectious death worldwide. gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (tb) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. to date most of these studies have focused on pulmonary tb patients with gene-expression profiles of extra-pulmonary tb patients yet to be compared to those of patients wi ...201627706152
metformin: candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients.despite major advances in tuberculosis (tb) control, tb continues to be a leading cause of death worldwide. the discovery of new anti-tb treatment drugs and regimens that target drug-sensitive and drug-resistant tb are being complemented with a search for adjunct host-directed therapies that synergize for mycobacterium tuberculosis (mtb) elimination. the goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit mtb grow ...201627720378
predictive value of serum bradykinin and desarg(9)-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: a retrospective case series.there is an urgent need for methods that can rapidly and accurately assess therapeutic responses in patients with active tuberculosis (tb) in order to predict treatment outcomes. exposure to bacterial pathogens can rapidly activate the plasma contact system, triggering the release of bradykinin (bk) and its metabolite desarg(9)-bradykinin (dabk) to induce inflammation and innate immune responses. we hypothesized that serum bk and dabk levels might act as sensitive immune response signatures for ...201627720377
pulmonary artery invasion caused by mycobacterium tuberculosis.extrapulmonary tuberculosis refers to mycobacterium tuberculosis involving organs other than the lungs (eg, pleura, lymph nodes, genitourinary tract, abdomen, skin, joints and bones, or meninges). in non-hiv-endemic areas, where reactivation is the predominant mechanism of tuberculosis, pleural involvement occurs in 4% of cases. we present an extremely rare case of a 62-year-old immunocompetent patient with pleural tuberculosis confirmed by surgical pleural biopsies, who presented with a large m ...201627719830
first characterization of the cd4 and cd8 t-cell responses to quantiferon-tb plus.quantiferon(®)-tb gold plus (qft-plus) is the new generation of quantiferon-tb gold in-tube test to identify latent tuberculosis infection (ltbi). qft-plus includes tb1 and tb2 tubes which contain selected mycobacterium tuberculosis (mtb) peptides designed to stimulate both cd4 and cd8 t-cells. aim of this study is the flow cytometric characterization of the specific cd4 and cd8 t-cell responses to mtb antigens contained within qft-plus.201627717779
chronic tuberculous otomastoiditis: a case report.worldwide, tuberculosis is a widespread disease, with 8.7 million new cases occurring annually. its etiologic agent, mycobacterium tuberculosis, essentially causes pneumonia. however, this organism affects the middle ear in rare cases, accounting for 0.04-0.09% of all chronic middle ear otitis cases in western countries. in this report, we describe the case of a young woman affected by tuberculosis of the middle ear. in our experience, empiric therapy was not beneficial. adequate treatment was p ...201627716611
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