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flow cytometry analysis of cd4+ifn-γ+ t-cells for the diagnosis of mycobacterium tuberculosis infection.cd4+ cells expressing interferon-γ (ifn-γ), following stimulation with specific mycobacterial antigens, identified with flow cytometry (fcm-cd4+ifn-γ+), is a new method for the diagnosis of mycobacterium tuberculosis (mtb) infection. the aim of this study is to investigate the performance of fcm-cd4+ifn-γ+ in comparison with tuberculin skin test (tst) and quantiferon tb gold in-tube (qft-g-it) in the diagnosis of latent mtb infection (ltbi), in close contacts and in patients with rheumatic disea ...201626202990
when and how to operate on spondylodiscitis: a report of 13 patients.conflicting reports exist regarding the surgical indications, timing, approach, staged or not operation, and spinal instrumentation for patients with spondylodiscitis. therefore, we performed this study to evaluate the outcome of a series of patients with spondylodiscitis aiming to answer when and how to operate on these patients.201626190644
characterization of lipn (rv2970c) of mycobacterium tuberculosis h37rv and its probable role in xenobiotic degradation.lipn (rv2970c) belongs to the lip family of m. tuberculosis h37rv and is homologous to the human hormone sensitive lipase. the enzyme demonstrated preference for short carbon chain substrates with optimal activity at 45°c/ph 8.0 and stability between ph 6.0-9.0. the specific activity of the enzyme was 217 u/mg protein with pnp-butyrate as substrate. it hydrolyzed tributyrin to di- and monobutyrin. the active-site residues of the enzyme were confirmed to be ser216, asp316, and his346. tetrahydrol ...201626212120
bisphosphonic acids as effective inhibitors of mycobacterium tuberculosis glutamine synthetase.inhibition of glutamine synthetase (gs) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. forty-three bisphosphonic and bis-h-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant gs from mycobacterium tuberculosis. most of the studied compounds exhibited activities in micromolar range, with n-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, n-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic ...201626235917
molecular structure and vibrational spectroscopic studies of prothionamide by density functional theory.prothionamide (pth) is the secondary drug used against mycobacterium tuberculosis bacteria and leprosy. the aim of this work was to investigate the potential energy surface map, anharmonic and harmonic vibrational spectra, nbo analysis and elf (electron localization function) of the title compound using dft approach with the b3lyp (becke, three-parameter, lee-yang-parr) exchange-correlation functional with the 6-31g++(d,p) and the z3polx basis sets were employed. in the experimental part of this ...201626219021
no significant impact of ifn-γ pathway gene variants on tuberculosis susceptibility in a west african population.the concept of interferon-γ (ifn-γ) having a central role in cell-mediated immune defence to mycobacterium tuberculosis has long been proposed. observations made through early candidate gene studies of constituents of the ifn-γ pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (tb). by analysing 20 major genes whose proteins contribute to ifn-γ signalling we have assessed a large fraction of the variability in genes that might con ...201626242990
the role of nucleotide-binding oligomerization domain 1 during cytokine production by macrophages in response to mycobacterium tuberculosis infection.tuberculosis due to mycobacterium tuberculosis infection is a leading cause of death worldwide. recognition of this pathogen is crucial for the activation of innate and adaptive immune responses. nucleotide-binding oligomerization domain (nod)1 and nod2 are cytoplasmic receptors that can detect unique muropeptides of bacterial peptidoglycan. nod2 is critical for the initiation of the host immune response against m. tuberculosis infection, however the role of nod1 remains largely unknown. we inve ...201626255090
comparison of clinical characteristics in patients with takayasu arteritis with and without concomitant tuberculosis.because of frequent tuberculosis in patients with takayasu arteritis (ta), a possible relationship between ta and tuberculosis has been proposed. however, there are no studies to date that have examined clinical manifestations in patients diagnosed with ta with or without tuberculosis. two hundred sixty-seven patients were diagnosed with ta according to the 1990 american college of rheumatology criteria between september 1994 and april 2014. patients with ta were classified into groups with or w ...201626266634
fibronectin binding protein and ca(2+) play an access key role to mediate pathogenesis in mycobacterium tuberculosis: an overview.the anomalous distribution of adhesive proteins throughout on the cell surface of the mycobacterium tuberculosis h37 rv and their contribution in cell surface adhesion and host-pathogen interaction remain elusive. the completion of m. tuberculosis h37 rv genome sequence analysis gives some interesting information about polymorphic gc-rich repetitive sequence (pgrs) subfamily of m. tuberculosis that encodes fibronectin binding proteins (fnbp), which have been extensively studied, but the function ...201626275158
design and development of mycobacterium tuberculosis lysine ɛ-aminotransferase inhibitors for latent tuberculosis infection.lysine ɛ-aminotransferase (lat) is a protein involved in lysine catabolism, and it plays a significant role during the persistent/latent phase of mycobacterium tuberculosis (mtb), as observed by its up-regulation by ~40-fold during this stage. we have used the crystal structure of mtb lat in external aldimine form in complex with its substrate lysine as a template to design and identify seven lead compounds with ic50 ranging from 18.06 to > 90 μm. we have synthesized 21 compounds based on the id ...201626348876
evaluation of heat shock proteins for discriminating between latent tuberculosis infection and active tuberculosis: a preliminary report.the diagnosis of a latent tuberculosis infection (ltbi) is of the utmost concern. the available tests, the tuberculin skin test (tst) and the quantiferon-tb gold test (qft-g) cannot discriminate between active tb and ltbi. therefore, the aim of the study is to identify new biomarkers that can discriminate between active tb and ltbi and can also assess the risk of the individual developing active tb. in total, 55 blood samples were collected, of which 10 samples were from the active tb infection ...201626300163
computational sampling and simulation based assessment of novel mycobacterium tuberculosis glutamine synthetase inhibitors: study involving structure based drug design and free energy perturbation.the highly persistent nature of mycobacterium tuberculosis can be attributed to its lipophilic cell wall which acts as a major barrier in the process of drug discovery against tuberculosis. glutamine synthetase plays a major role in nitrogen metabolism and cell wall biosynthesis of pathogenic mycobacteria. the current review focuses on the structural and functional aspects of mtb glutamine synthetase and an overview of its reported inhibitors till date. also in the present study, we employed a c ...201626303425
[analysis of mutation in codon 531 rpob gene, associated with rifampicin resistance among samples of mycobacterium tuberculosis that was isolated from the patients].in the conditions of high relative density of multidrug resistant tuberculosis in ukraine, rapid diagnostics of m. tuberculosis susceptibility to antituberculous drugs is the important tool in treatment of patients with lung tuberculosis. 78 patients with lung tb that were treated in tb dispensary in kharkiv during 2004-2005 years were analyzed. mutations in 531 codon of rpob gene of isolates m. tuberculosis were studied. among 48 (61.5%) resistant isolates of m tuberculosis according to phenoty ...201626118085
tuberculosis in immigrants in finland, 1995-2013.increasing immigration from high tuberculosis (tb) incidence countries is a challenge for surveillance and control in finland. here, we describe the epidemiology of tb in immigrants by using national surveillance data. during 1995-2013, 7030 (84·7%) native and 1199 (14·4%) immigrant cases were identified. the proportion of immigrant cases increased from 5·8% in 1995 to 32·1% in 2013, consistent with increasing immigrant population (2·1-5·6%) and decreasing incidence of tb in the native populatio ...201626135388
insight into the structural requirements of aminopyrimidine derivatives for good potency against both purified enzyme and whole cells of m. tuberculosis: combination of hqsar, comsia, and md simulation studies.the mycobacterium tuberculosis protein kinase b (pknb) is critical for growth and survival of m. tuberculosis within the host. the series of aminopyrimidine derivatives show impressive activity against pknb (ic50 < .5 μm). however, most of them show weak or no cellular activity against m. tuberculosis (mic > 63 μm). consequently, the key structural features related to activity against of both pknb and m. tuberculosis need to be investigated. here, two- and three-dimensional quantitative structur ...201626156406
genotype heterogeneity of mycobacterium tuberculosis within geospatial hotspots suggests foci of imported infection in sydney, australia.in recent years the state of new south wales (nsw), australia, has maintained a low tuberculosis incidence rate with little evidence of local transmission. nearly 90% of notified tuberculosis cases occurred in people born in tuberculosis-endemic countries. we analyzed geographic, epidemiological and genotypic data of all culture-confirmed tuberculosis cases to identify the bacterial and demographic determinants of tuberculosis hotspot areas in nsw. standard 24-loci mycobacterium interspersed rep ...201626187743
consensus document on prevention and treatment of tuberculosis in patients for biological treatment.tuberculosis risk is increased in patients with chronic inflammatory diseases receiving any immunosuppressive treatment, notably tumor necrosis factor (tnf) antagonists therapy. screening for the presence of latent infection with mycobacterium tuberculosis and targeted preventive treatment to reduce the risk of progression to tb is mandatory in these patients. this consensus document summarizes the current knowledge and expert opinion of biologic therapies including tnf-blocking treatments. it p ...201626187708
mathematical model of oxygen transport in tuberculosis granulomas.pulmonary granulomas--the hallmark of mycobacterium tuberculosis (mtb) infection--are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. low oxygen in granulomas can impair the host immune response, while mtb are able to adapt and persist in hypoxic environments. here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming michaelis-men ...201626253038
cloning and characterization of a novel pe_pgrs60 protein (rv3652) of mycobacterium tuberculosis h37 rv exhibit fibronectin-binding property.the binding of pathogenic bacteria to extracellular matrix components enhances adhesion and invasion of host cells. the host receptor proteins such as fibronectin (fn) targeted to pathogenic ligands that have clinical importance. in the present study, we cloned, expressed, purified, and identified a novel fn-binding protein from pe_pgrs60 (rv3652) of mycobacterium tuberculosis h37 rv. the protein product of rv3652 showed optimum binding efficiency to 10 ng fn at 0.2 µg purified protein of pe_pgr ...201626158346
fighting an old disease with modern tools: characteristics and molecular detection methods of drug-resistant mycobacterium tuberculosis.tuberculosis (tb) is an ancient disease, but not a disease of the past. the increasing prevalence of drug-resistant strains of mycobacterium tuberculosis, the causative agent of tb, demands new measures to combat the situation. rapid and accurate detection of the pathogen, and its drug susceptibility pattern, is essential for timely initiation of treatment, and ultimately, control of the disease. molecular-based methods offer a great chance to improve detection of drug-resistant tb; however, the ...201626167849
the rlrp of mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates apc function in mouse macrophages via a tlr2-mediated pi3k/akt pathway activation-dependent mechanism.we demonstrate that mycobacterium tuberculosis recombinant leucine-responsive regulatory protein (rlrp) inhibits lipopolysaccharide (lps)-induced tumor necrosis factor alpha (tnf-α), interleukin-6, and interleukin-12 production and blocks the nuclear translocation of subunits of the nuclear-receptor transcription factor nf-κb (nuclear factor-kappa b). moreover, rlrp attenuated lps-induced dna binding and nf-κb transcriptional activity, which was accompanied by the degradation of inhibitory iκbα ...201626166760
the discovery, function and development of the variable number tandem repeats in different mycobacterium species.the method of genotyping by variable number tandem repeats (vntrs) facilitates the epidemiological studies of different mycobacterium species worldwide. until now, the vntr method is not fully understood, for example, its discovery, function and classification. the inconsistent nomenclature and terminology of vntr is especially confusing. in this review, we first describe in detail the vntrs in mycobacterium tuberculosis (m. tuberculosis), as this pathogen resulted in more deaths than any other ...201626089025
fitness costs of drug resistance mutations in multidrug-resistant mycobacterium tuberculosis: a household-based case-control study.the projected long-term prevalence of multidrug-resistant (mdr) tuberculosis depends upon the relative fitness of mdr mycobacterium tuberculosis strains, compared with non-mdr strains. while many experimental models have tested the in vitro or in vivo fitness costs of various drug resistance mutations, fewer epidemiologic studies have attempted to validate these experimental findings.201626092854
second-line anti-tuberculosis drug resistance and its genetic determinants in multidrug-resistant mycobacterium tuberculosis clinical isolates.mutations in several genetic loci have been implicated in the development of resistance to second-line anti-tuberculosis (tb) drugs (slds). the purpose of this study was to investigate the prevalence of resistance to slds and its association with specific mutations in multidrug-resistant (mdr) mycobacterium tuberculosis clinical isolates.201626117528
treatment of latent tuberculosis infection induces changes in multifunctional mycobacterium tuberculosis-specific cd4+ t cells.to ascertain whether multiparametric flow cytometry assessment of multifunctional mycobacterium tuberculosis (mtb)-specific cd4(+) and cd8(+) t cells can distinguish between untreated and treated patients with latent tuberculosis infection (ltbi), we enrolled 14 ltbi subjects treated with isoniazid (inh) therapy, 16 untreated ltbi patients, and 25 healthy controls. the analysis of mono-functional cd4(+) and cd8(+) t cells producing single cytokines showed significant differences only between uni ...201626108901
boosting bcg-primed mice with chimeric dna vaccine hg856a induces potent multifunctional t cell responses and enhanced protection against mycobacterium tuberculosis.the tuberculosis pandemic continues to rampage despite widespread use of the current bacillus calmette-guerin (bcg) vaccine. because dna vaccines can elicit effective antigen-specific immune responses, including potent t cell-mediated immunity, they are promising vehicles for antigen delivery. in a prime-boost approach, they can supplement the inadequate anti-tb immunological memory induced by bcg. based on this, a chimeric dna vaccine hg856a encoding mycobacterium tuberculosis (m. tuberculosis) ...201626111521
high prevalence of primary drug resistance in children with intrathoracic tuberculosis in india.drug susceptibility testing (dst) of mycobacterium tuberculosis (mtb) isolates is crucial for the effective treatment of tuberculosis. data on dst patterns in mtb isolates in childhood tuberculosis are scanty.201626052730
factors influencing delayed health care seeking among pulmonary tuberculosis suspects in rural communities in ntcheu district, malawi.delayed diagnosis and treatment of tuberculosis (tb) among individuals suspected of having tb may lead to continued transmission of mycobacterium tuberculosis in communities, higher mortality rates, and increase in government health expenditure because of prolonged illness due to late diagnosis and treatment initiation. the study explored factors leading to delayed health care seeking among individuals living in ntcheu district, malawi. two key informant interviews, 16 in-depth interviews, and t ...201626015428
structural analysis of sigma e interactions with core rna polymerase and its cognate p-hsp20 promoter of mycobacterium tuberculosis.alternate sigma factor plays an important role for the survival of mycobacterium tuberculosis in adverse environmental condition. stress-induced sigma factors are major cause for expression of genes involved in pathogenesis, dormancy and various unusual environmental conditions. in the present work, an attempt has been made to characterize one of such m. tuberculosis (mtb) sigma factor, sige. the structures of mtb-sige and mtb-β have been predicted using comparative modelling techniques and vali ...201626006066
mutational analysis of mycobacterium tuberculosis lysine ɛ-aminotransferase and inhibitor co-crystal structures, reveals distinct binding modes.lysine ɛ-aminotransferase (lat) converts lysine to α-aminoadipate-δ-semialdehyde in a plp-mediated reaction. we mutated active-site t330, n328 and e243, and structurally rationalized their properties. t330a and t330s mutants cannot bind plp and are inactive. n328a although inactive, binds to plp. e243a retains activity, but binds α-ketoglutarate in a different conformation. we had earlier identified 2-aminomethyl piperidine derivative as a lat inhibitor. the co-crystal structure reveals that it ...201626003725
indole-based hydrazide-hydrazones and 4-thiazolidinones: synthesis and evaluation as antitubercular and anticancer agents.a new series of indolylhydrazones (6) and indole-based 4-thiazolidinones (7, 8) have been designed, synthesized and screened for in vitro antitubercular activity against mycobacterium tuberculosis h37rv. 4-thiazolidinone derivatives 7g-7j, 8g, 8h and 8j displayed notable antituberculosis (anti-tb) activity showing 99% inhibition at mic values ranging from 6.25 to 25.0 µg/ml. compounds 7g, 7h, 7i, 8h and 8j demonstrated anti-tb activity at concentrations 10-fold lower than those cytotoxic for the ...201625910087
the prospective evaluation of the tb strain typing service in england: a mixed methods study.in response to rising tb notification rates in england, universal strain typing was introduced in 2010. we evaluated the acceptability, effectiveness and cost-effectiveness of the tb strain typing service (tb-sts).201625882538
identifying areas and risk groups with localised mycobacterium tuberculosis transmission in northern england from 2010 to 2012: spatiotemporal analysis incorporating highly discriminatory genotyping data.information on geographical variation in localised transmission of tb can inform targeting of disease control activities. the aim of this study was to estimate the proportion of tb attributable to localised transmission for the period 2010-2012 in northern england and to identify case characteristics associated with spatiotemporal-genotypical clusters.201625920328
synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives.a study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c][4,7]phenanthroline skeleton is described. the strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. stereo- and regiochemistry of cycloaddition reactions were discussed. the structure of the new compounds was proven unambiguou ...201625945747
new pimarane diterpenes and other antimycobacterial metabolites from anisochilus verticillatus.phytochemical investigation of the acetone extract of the aerial parts of anisochilus verticillatus afforded a new 8,9-secopimarane diterpene (1), two new isopimarane diterpenes (2, 3) and the known ursolic acid (4), α-amyrin (5), β-amyrin (6), stigmast-5-en-3-one (7) and hydroxychavicol (8). structures of the new compounds were elucidated with the help of 1d and 2d nuclear magnetic resonance spectroscopic data, and single crystal x-ray crystallography of compound 3. compounds 2 and 8 inhibited ...201625978136
targeting the cell wall of mycobacterium tuberculosis: a molecular modeling investigation of the interaction of imipenem and meropenem with l,d-transpeptidase 2.the single crystal x-ray structure of the extracellular portion of the l,d-transpeptidase (ex-ldtmt2 - residues 120-408) enzyme was recently reported. it was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating l,d-transpeptide linkages in the peptidoglycan layer of mycobacterium tuberculosis. imipenem is more active and isothermal titration calorimetry experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. h ...201625762064
[computed tomography pattern of unchanged mediastinal lymph nodes in children with uninfected mycobacterium tuberculosis].to provide x-ray characteristics of mediastinal lymph nodes revealed by computed tomography (ct) in children and adolescents with uninfected mycobacterium tuberculosis.201625775884
[role of laparoscopy in the diagnosis of peritoneal tuberculosis in endemic areas].the aim of our study is to demonstrate the difficulties of diagnosis of peritoneal tuberculosis in endemic areas and the value of laparoscopy for diagnostic confirmation. we report a retrospective study of 60 cases of peritoneal tuberculosis, collected from january 2004 to december 2009. the patients' median age was 41 years, and the sex ratio 0.4. the dominant reasons for consultation were pain and abdominal distension. abdominal ultrasound found ascites in all patients. computed tomography (ct ...201625787316
distinct strategies employed by dendritic cells and macrophages in restricting mycobacterium tuberculosis infection: different philosophies but same desire.dendritic cells (dcs) and macrophages (mϕs) are professional antigen-presenting cells (apcs) that can efficiently phagocytose mycobacterium tuberculosis (mtb), the etiological agent of tuberculosis (tb). it is quite interesting to mention here that dcs and mϕs use distinct strategies to combat and eliminate mtb. similarly, mtb employs different mechanisms to counteract the action of dcs and mϕs. mϕs are evolved with specialized, innate, defensive machinery to restrict growth of mtb at the initia ...201625793750
distribution and function of prophage phirv1 and phirv2 among mycobacterium tuberculosis complex.mycobacterium tuberculosis complex (mtbc) is notorious for causing diseases, such as tuberculosis. tuberculosis caused by m. tuberculosis remains a global public health concern. two prophages, phirv1 and phirv2, can be found among most mtbc genomes. however, no precise functions have been assigned for the two prophages. in this paper, to find out the function of these two prophages, the distribution and function of phirv1 and phirv2 in mtbc genomes were analyzed from multiple omics data. we foun ...201625855385
[analysis of genetic determinants of multidrug and extensively drug-resistant mycobacterium tuberculosis using oligonucleotide microchip].steadily growing resistance of the tuberculosis causative agent towards a broad spectrum of anti-tuberculosis drugs calls for rapid and reliable methods for identifying the genetic determinants responsible for this resistance. in this study, we present a biochip-based method for simultaneous identification of mutations within rpob gene associated with rifampin resistance, mutations in katg, inha, ahpc genes responsible for isoniazid resistance, mutations within the regions of gyra and gyrb genes ...201625850294
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
antibiotic methylation: a new mechanism of antimicrobial resistance.in new research on mycobacterium tuberculosis, the causative agent of tuberculosis, warrier and colleagues have discovered a novel mode of bacterial drug resistance, namely antibiotic inactivation via n-methylation.201627593675
strategies to enhance immunogenicity of cdna vaccine encoded antigens by modulation of antigen processing.most vaccines are based on protective humoral responses while for intracellular pathogens cd8(+) t cells are regularly needed to provide protection. however, poor processing efficiency of antigens is often a limiting factor in cd8(+) t cell priming, hampering vaccine efficacy. the multistage cdna vaccine h56, encoding three secreted mycobacterium tuberculosis antigens, was used to test a complete strategy to enhance vaccine' immunogenicity. potential cd8(+) t cell epitopes in h56 were predicted ...201627593157
immune response to mycobacterium tuberculosis in young contacts with discordant immunological test results. 201627592265
synthesis and evaluation of copper(ii) complexes with isoniazid-derived hydrazones as anticancer and antitubercular agents.in this study, the n,n,o metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (hpcih, 1) and its derivatives 2-acetylpyridine-(hapih 2), 2-pyridineformamide-(hpamih, 3) and pyrazineformamide-(hpzamih, 4) were employed in the synthesis of four copper(ii) complexes, [cu(hpcih)cl2]·0.4h2o (5), [cu(hapih)cl2]·1.25h2o (6), [cu(hpamih)cl2]·h2o (7) and [cu(hpzamih)cl2]·1.25h2o (8). the compounds were assayed for their action toward mycobacterium tuberculosis h37rv atcc 27294 strain and the hu ...201627591998
virtual screening and x-ray crystallography identify non-substrate analog inhibitors of flavin-dependent thymidylate synthase.thymidylate synthase x (thyx) represents an attractive target for tuberculosis drug discovery. herein, we selected 16 compounds through a virtual screening approach. we solved the first x-ray crystal structure of thermatoga maritima (tm) thyx in complex with a nonsubstrate analog inhibitor. given the active site similarities between mycobacterium tuberculosis thyx (mtb-thyx) and tm-thyx, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. the 1h ...201627589670
identifying components for programmatic latent tuberculosis infection control in the european union.individuals with latent tuberculosis infection (ltbi) are the reservoir of mycobacterium tuberculosis in a population and as long as this reservoir exists, elimination of tuberculosis (tb) will not be feasible. in 2013, the european centre for disease prevention and control (ecdc) started an assessment of benefits and risks of introducing programmatic ltbi control, with the aim of providing guidance on how to incorporate ltbi control into national tb strategies in european union/european economi ...201627589214
necrotic cell sensor clec4e promotes a proatherogenic macrophage phenotype through activation of the unfolded protein response.atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. c-type lectin receptor 4e (clec4e) recognizes the cord factor of mycobacterium tuberculosis but also senses molecular patterns rel ...201627587433
analysis of the contribution of mtp and the predicted flp pilus genes to mycobacterium tuberculosis pathogenesis.mycobacterium tuberculosis (mtb) is one of the world's most successful pathogens. millions of new cases of tuberculosis occur each year, emphasizing the need for better methods of treatment. the design of novel therapeutics is dependent on our understanding of factors that are essential for pathogenesis. many bacterial pathogens use pili and other adhesins to mediate pathogenesis. the recently identified mycobacterium tuberculosis pilus (mtp) and the hypothetical, widely conserved flp pilus have ...201627586540
enhanced immune response of mait cells in tuberculous pleural effusions depends on cytokine signaling.the functions of mait cells at the site of mycobacterium tuberculosis infection in humans are still largely unknown. in this study, the phenotypes and immune response of mait cells from tuberculous pleural effusions and peripheral blood were investigated. mait cells in tuberculous pleural effusions had greatly enhanced ifn-γ, il-17f and granzyme b response compared with those in peripheral blood. the level of ifn-γ response in mait cells from tuberculous pleural effusions was inversely correlate ...201627586092
the genotypic study of mycobacterium tuberculosis complex resistant to isoniazid: galicia, spain (2008-2013).incorporation of rapid detection systems to identify mutations in m. tuberculosis complex that confer resistance to isoniazid and rifampicin has potentiated the knowledge of their distribution, given the geographical variability. we performed antibiograms of the 2,993 strains isolated in galicia, spain (2008-2013). in the strains resistant to isoniazid, a concentration of 0.4 mg/ml and mtbdrplus genotype test (hain lifescience, germany) were used. we found that 3.64 % of strains were resistant t ...201627586016
microwave-assisted synthesis of 2-styrylquinoline-4-carboxylic acids as antitubercular agents.many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies.201627585570
effects of mbl-associated serine protease-2 (masp-2) on liquefaction and ulceration in rabbit skin model of tuberculosis.tuberculosis is a chronic infectious disease, which caused by mycobacterium tuberculosis. it typically affects the functions of the lung and causes high morbidity and mortality rates worldwide. the lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. however, what is the specific effection between tuberculosis and complement is unknown. mannose-binding lectin (mbl), a recognition subunit, binds to arrays of carbohydrates on the s ...201627585546
drug susceptibility patterns of the mycobacterium tuberculosis isolated from previously treated and new cases of pulmonary tuberculosis at german-nepal tuberculosis project laboratory, kathmandu, nepal.multidrug resistant tuberculosis (mdr-tb) is a serious public health problem in nepal. it is a major obstacle for the control of the tuberculosis. the main objectives of this study were to determine the prevalence of the multidrug resistant pulmonary tuberculosis and to evaluate the drug susceptibility patterns of mycobacterium tuberculosis isolated from previously treated and newly diagnosed cases of pulmonary tuberculosis.201627583136
[tuberculous pyopneumothorax: about 18 cases].tuberculous pyopneumothorax is a rare but serious complication of evolutive pulmonary tuberculosis. we report a series of 18 cases with tuberculous pyopneumothorax admitted to the pneumo-phthisiology department of the mohammed v military teaching hospital in rabat between january 2005 and december 2009. our study included 15 men and 3 women, the average age was 35 ± 7 years. 4 patients were diabetic. smoking was found in 9 cases. right-sided pneumothorax was found in 13 cases. chest radiograph s ...201627583090
patterns of drug resistance among tuberculosis patients in west and northwestern iran.tuberculosis (tb) is the leading cause of morbidity and mortality among chronic infectious diseases.201627583054
insights into horizontal acquisition patterns of dormancy and reactivation regulon genes in mycobacterial species using a partitioning-based framework.horizontal gene transfer (hgt) events, initially thought to be rare in mycobacterium tuberculosis, have recently been shown to be involved in the acquisition of virulence operons in m. tuberculosis. we have developed a new partitioning framework based hgt prediction algorithm, called grid3m, and applied the same for the prediction of hgts in mycobacteria. validation and testing using simulated and real microbial genomes indicated better performance of grid3m as compared with other widely used hg ...201627581938
smear positive pulmonary tuberculosis and associated factors among homeless individuals in dessie and debre birhan towns, northeast ethiopia.tuberculosis (tb) remains one of the globe's deadliest communicable diseases. the homeless individuals are at high risk to acquire tb and multi-drug resistant tb (mdr-tb), because of their poor living conditions and risky behaviors. tuberculosis and mdr-tb in the homeless individuals can pose a risk to entire communities. however, the magnitude of the problem is not known in ethiopia. therefore, the aim of this study was to determine the prevalence and associated factors of smear positive pulmon ...201627581729
identification of kasa as the cellular target of an anti-tubercular scaffold.phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. in this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (gsk3011724a) identifies several specific single-nucleotide polymorphisms in the essential mycobacterium tuberculosis β-ketoacyl synthase (kas) a gene. here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of ...201627581223
ifn-γ release assay result is associated with disease site and death in active tuberculosis.the ifn-γ release assays and tuberculin skin tests are used to support the diagnosis of both latent and active tuberculosis. however, we previously demonstrated that a negative tuberculin test in active tuberculosis is associated with disseminated disease and death. it is unknown whether the same associations exist for ifn-γ release assays.201627580246
propargyl-linked antifolates are potent inhibitors of drug-sensitive and drug-resistant mycobacterium tuberculosis.mycobacterium tuberculosis continues to cause widespread, life-threatening disease. in the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (mdr and xdr) bacteria have spread globally and the number of agents that effectively treat these infections is significantly reduced. we have been developing the propargyl-linked antifolates (plas) as potent inhibitors of the essential enzyme dihydrofolate reductase (dhfr) from bacteria and recently found that charged ...201627580226
shedding light on the performance of a pyrosequencing assay for drug-resistant tuberculosis diagnosis.rapid molecular diagnostics, with their ability to quickly identify genetic mutations associated with drug resistance in mycobacterium tuberculosis clinical specimens, have great potential as tools to control multi- and extensively drug-resistant tuberculosis (m/xdr-tb). the qiagen pyromark q96 id system is a commercially available pyrosequencing (psq) platform that has been validated for rapid m/xdr-tb diagnosis. however, the details of the assay's diagnostic and technical performance have yet ...201627576542
gene therapy based in antimicrobial peptides and proinflammatory cytokine prevents reactivation of experimental latent tuberculosis.mycobacterium tuberculosis (mtb) latent infection can lead to reactivation. the design of new strategies to prevent it is an important subject. b6d2f1 mice were infected intratracheally with a low dose of mtb h37rv to induce chronic infection. after 7 months, mice were treated with one dose of recombinant adenoviruses encoding tnfα, β defensin-3 and ll37. immunosupression was induced 1 month later with corticosterone. in comparison with the control group, mice treated with adenoviruses showed si ...201627604468
high ifn-γ release and impaired capacity of multi-cytokine secretion in igra supernatants are associated with active tuberculosis.interferon gamma (ifn-γ) release assays (igras) detect mycobacterium tuberculosis (mtb) infection regardless of the active (atb) or latent (ltbi) forms of tuberculosis (tb). in this study, mtb-specific t cell response against region of deletion 1 (rd1) antigens were explored by a microbead multiplex assay performed in t-spot tb assay (t-spot) supernatants from 35 patients with atb and 115 patients with ltbi. t-spot is positive when over 7 ifn-γ secreting cells (sc)/250 000 peripheral blood monon ...201627603919
investigating the reaction mechanism of f420-dependent glucose-6-phosphate dehydrogenase from mycobacterium tuberculosis: kinetic analysis of the wild-type and mutant enzymes.f420-dependent glucose-6-phosphate dehydrogenase (fgd) catalyzes the conversion of glucose-6-phosphate (g6p) to 6-phosphogluconolactone, using f420 cofactor as the hydride transfer acceptor, within mycobacteria. a previous crystal structure of wild-type fgd led to a proposed mechanism suggesting that the active site residues his40, trp44, and glu109 could be involved in catalysis. we have characterized the wild-type fgd and five fgd variants (h40a, w44f, w44y, w44a, and e109q) by fluorescence bi ...201627603793
design, synthesis, and characterization of (1-(4-aryl)- 1h-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against mycobacterium tuberculosis.the novel (1-(4-aryl)-1h-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of cu(oac)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. the newly synthesized compounds were characterized by a number of spectroscopic techniques, ...201627601885
bis-biguanide dihydrochloride inhibits intracellular replication of m. tuberculosis and controls infection in mice.while there is an urgent need to develop new and effective drugs for treatment of tuberculosis (tb) and multi-drug resistant tb (mdr-tb), repurposing fda (u.s. food and drug administration) -approved drugs for development of anti-tb agents may decrease time and effort from bench to bedside. here, we employed host cell-based high throughput screening (hts) assay to screen and characterize fda-approved, off-patent library drugs for anti-mycobacterium tuberculosis (mtb) activities. the cell-based h ...201627601302
pyrazinamide resistance assays and two-month sputum culture status in patients with multidrug-resistant tuberculosis.phenotypic drug susceptibility testing is the current "gold standard" for detecting mycobacterium tuberculosis susceptibility to antituberculous drugs. pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. here we performed latent class analysis (lca) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. we then compared this consensus m ...201627600032
culture and reverse transcriptase polymerase chain reaction (rt-pcr) proven mycobacterium tuberculosis endophthalmitis: a case series.to report early confirmation of mycobacterium tuberculosis (mtb) endophthalmitis by detection of 85b mrna in vitreous by a reverse transcriptase polymerase chain reaction (rt-pcr) technique.201627598944
[spondylodiscitis: clinical experience in a chilean general hospital].spondylodiscitis (sd) involves long periods of hospitalization, diagnostic latency and risk of long-term complications. no updated series are available in chile and a change in demographic features and etiology is suspected.201627598284
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
crystal structure of vapc21 from mycobacterium tuberculosis at 1.31 å resolution.persisters are individual bacterial cells that exhibit a phenotype characterized by slow growth, low metabolic rate and multidrug tolerance. the processes that drive cells into a persistence state constitute an active but incipient research field, and structural data regarding its components are scarce. the molecular targets of many therapeutic drugs are involved in cell wall synthesis and cell division, and these cellular processes are down-regulated in persister cells, consequently these cells ...201627576202
plasma adenosine deaminase enzyme reduces with treatment of pulmonary tuberculosis in nigerian patients: indication for diagnosis and treatment monitoring.tuberculosis(tb)-specific host biomarkers for diagnosis and monitoring of treatment response have been identified as priorities for tb research. macrophage and t cell lymphocytes play vital roles in mycobacterium tuberculosis immune response and their associated biomarkers could form good candidates for diagnosis and treatment monitoring. the enzyme adenosine deaminase (ada) is produced mainly by monocytes and macrophages and increase in biological fluids in the course of infection with microorg ...201627574764
network analysis identifies rv0324 and rv0880 as regulators of bedaquiline tolerance in mycobacterium tuberculosis.the resilience of mycobacterium tuberculosis (mtb) emerges from its ability to effectively counteract immunological, environmental and antitubercular challenges. here, we demonstrate that mtb can tolerate drug treatment by adopting a tolerant state that can be deciphered through systems analysis of its transcriptional responses. specifically, we demonstrate how treatment with the antitubercular drug bedaquiline activates a regulatory network that coordinates multiple resistance mechanisms to pus ...201627573104
structural insight into dephosphorylation by trehalose 6-phosphate phosphatase (otsb2) from mycobacterium tuberculosis.trehalose serves as a key structural component in the cell wall of mycobacterium tuberculosis. m. tuberculosis trehalose-6-phosphate phosphatase (mtbtpp), an essential enzyme in the trehalose biosynthesis otsab pathway, catalyzes the dephosphorylation of trehalose-6-phosphate (trehalose-6-p) to generate trehalose, and plays a critical role in m. tuberculosis survival-associated cell wall formation and permeability. therefore, mtbtpp (otsb2) is considered a promising potential target for discover ...201627572957
role of cathepsins in mycobacterium tuberculosis survival in human macrophages.cathepsins are proteolytic enzymes that function in the endocytic pathway, especially in lysosomes, where they contribute directly to pathogen killing or indirectly, by their involvement in the antigen presentation pathways. mycobacterium tuberculosis (mtb) is a facultative intracellular pathogen that survives inside the macrophage phagosomes by inhibiting their maturation to phagolysosomes and thus avoiding a low ph and protease-rich environment. we previously showed that mycobacterial inhibiti ...201627572605
bioluminescent reporters for rapid mechanism of action assessment in tuberculosis drug discovery.the tuberculosis (tb) drug discovery pipeline is fueled by compounds identified in whole-cell screens against the causative agent, mycobacterium tuberculosis phenotypic screening enables the selection of molecules that inhibit essential cellular functions in live, intact bacilli grown under a chosen in vitro condition. however, deducing the mechanism of action (moa), which is important to avoid promiscuous targets, often requires significant biological resources in a lengthy process that risks d ...201627572410
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