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fragment-based approaches to the development of mycobacterium tuberculosis cyp121 inhibitors.the essential enzyme cyp121 is a target for drug development against antibiotic resistant strains of mycobacterium tuberculosis. a triazol-1-yl phenol fragment 1 was identified to bind to cyp121 using a cascade of biophysical assays. synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (kd = 15 μm). deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identifica ...201627002486
structural analysis of the dodecameric proteasome activator pafe in mycobacterium tuberculosis.the human pathogen mycobacterium tuberculosis (mtb) requires a proteasome system to cause lethal infections in mice. we recently found that proteasome accessory factor e (pafe, rv3780) activates proteolysis by the mtb proteasome independently of adenosine triphosphate (atp). moreover, pafe contributes to the heat-shock response and virulence of mtb here, we show that pafe subunits formed four-helix bundles similar to those of the eukaryotic atp-independent proteasome activator subunits of pa26 a ...201627001842
latin-american-mediterranean lineage of mycobacterium tuberculosis: human traces across pathogen's phylogeography.currently, mycobacterium tuberculosis isolates of latin-american mediterranean (lam) family may be detected far beyond the geographic areas that coined its name 15years ago. here, we established the framework phylogeny of this geographically intriguing and pathobiologically important mycobacterial lineage and hypothesized how human demographics and migration influenced its phylogeography. phylogenetic analysis of lam isolates from all continents based on 24 variable number of tandem repeats (vnt ...201627001605
integration of metabolic modeling with gene co-expression reveals transcriptionally programmed reactions explaining robustness in mycobacterium tuberculosis.robustness of metabolic networks is accomplished by gene regulation, modularity, re-routing of metabolites and plasticity. here, we probed robustness against perturbations of biochemical reactions of m. tuberculosis in the form of predicting compensatory trends. in order to investigate the transcriptional programming of genes associated with correlated fluxes, we integrated with gene co-expression network. knock down of the reactions nadh2r and atps responsible for producing the hub metabolites, ...201627000948
two ways to skin a cat: acyldepsipeptides antibiotics can kill bacteria through activation or inhibition of clpp activity.infection by mycobacterium tuberculosis (mtb) has had a devastating effect on the world population. acyldepsipeptide antibiotics (adeps) are known to kill some bacteria by over activating the bacterial clpp peptidase. adep antibiotics also target mtb, with the assumption that uncontrolled adep-activated proteolysis by clpp is the common mode of killing. in this issue of molecular microbiology, famulla, et al. now show that adep's effectiveness in mycobacteria is likely due to inhibition of clpp- ...201627000447
csor is essential for maintaining copper homeostasis in mycobacterium tuberculosis.mycobacterium tuberculosis, a pathogen infecting one third of the world population, faces numerous challenges within the host, including high levels of copper. we have previously shown that m. tuberculosis csor is a copper inducible transcriptional regulator. here we examined the hypothesis that csor is necessary for maintaining copper homeostasis and surviving under various stress conditions. with an unmarked csor knockout strain, we were able to characterize the role of csor in m. tuberculosis ...201626999439
synthesis and structural insight into esx-1 substrate protein c, an immunodominant mycobacterium tuberculosis-secreted antigen.tuberculosis, the second leading cause of death from a single infectious agent, is recognized as a major threat to human health due to a lack of practicable vaccines against the disease and the widespread occurrence of drug resistance. with a pressing need for a novel protein target as a platform for new vaccine development, esx-1 substrate protein c (espc) was recently identified as a novel mycobacterium tuberculosis-secreted antigen that is as immunodominant as the two specific immunodiagnosti ...201626999334
accurate detection of rifampicin-resistant mycobacterium tuberculosis strains.in 2013 alone, the death rate among the 9.0 million people infected with mycobacterium tuberculosis (tb) worldwide was around 14%, which is unacceptably high. an empiric treatment of patients infected with tb or drug-resistant mycobacterium tuberculosis (mdr-tb) strain can also result in the spread of mdr-tb. the diagnostic tools which are rapid, reliable, and have simple experimental protocols can significantly help in decreasing the prevalence rate of mdr-tb strain. we report the evaluation of ...201626999135
efficacy and effect of free treatment on multidrug-resistant tuberculosis.multidrug-resistant tuberculosis (mdr-tb) is a serious public health and social issue. it pertains to the type of tuberculosis that is resistant simultaneously to isoniazid and rifampicin. mdr-tb has a high mortality and is expensive to treat. the aim of the present study was to examine the therapeutic effects of individualized free treatment and the relevant influencing factors on the treatment outcome for mdr-tb. a prospective study module was used to analyze the therapeutic outcome of mdr-tb ...201626997992
post-exposure vaccination with the vaccine candidate bacillus calmette-guérin δurec::hly induces superior protection in a mouse model of subclinical tuberculosis.the tuberculosis vaccine bcg δurec::hly is the most advanced bcg replacement candidate in phase ii clinical development. here we assess the protective capacity of the construct administered to mice as homologous prime-boost vaccine prior mycobacterium tuberculosis infection and as post-exposure vaccine. multiple immunization did not improve the superior protection of bcg δurec::hly over bcg. animals with subclinical tuberculosis were better protected when vaccinated with bcg δurec::hly as compar ...201626994939
in vitro evaluation of the cyto-genotoxic potential of ruthenium(ii) scar complexes: a promising class of antituberculosis agents.tuberculosis is a top infectious disease killer worldwide, caused by the bacteria mycobacterium tuberculosis. increasing incidences of multiple drug-resistance (mdr) strains are emerging as one of the major public health threats. however, the drugs in use are still incapable of controlling the appalling upsurge of mdr. in recent years a marked number of research groups have devoted their attention toward the development of specific and cost-effective antimicrobial agents against targeted mdr-tub ...201626994489
bioassay-guided isolation and structural modification of the anti-tb resorcinols from ardisia gigantifolia.tuberculosis (tb) is a highly contagious disease mainly caused by mycobacterium tuberculosis h37 rv . antitubercular (anti-tb) bioassay-guided isolation of the chcl3 extract of the leaves and stems of the medicinal plant ardisia gigantifolia led to the isolation of two anti-tb 5-alkylresorcinols, 5-(8z-heptadecenyl) resorcinol (1) and 5-(8z-pentadecenyl) resorcinol (2). we further synthesized 15 derivatives based on these two natural products. these compounds (natural and synthetic) were evaluat ...201626992112
minor contribution of inha-15 mutations to the rapid detection of isoniazid resistance in mycobacterium tuberculosis isolates. 201626989290
modeling granulomas in response to infection in the lung.alveolar macrophages play a large role in the innate immune response of the lung. however, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, which includes activated macrophages and lymphocytes, particularly t cells, is called upon to control the pathogens. this collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like mycobacterium tuberc ...201626986986
establishment of an effective tlc bioautographic method for the detection of mycobacterium tuberculosis h37ra phosphoglucose isomerase inhibition by phosphoenolpyruvate.a bioautographic assay based on thin layer chromatography was developed for phosphoenolpyruvate (pep) detecting as a known but rarely studied inhibitor of phosphoglucose isomerase (pgi). the protocol with nadp(+)/nbt/pms (β-nicotinamide adenine dinucleotide phosphate/nitrotetrazolium blue chloride/phenazine methosulfate) staining was capable of detecting mycobacterium tuberculosis h37ra pgi inhibition using pep. according to this method, visibly brighter spots (zones) against purple background a ...201626986942
in vivo molecular dissection of the effects of hiv-1 in active tuberculosis.increased risk of tuberculosis (tb) associated with hiv-1 infection is primarily attributed to deficient t helper (th)1 immune responses, but most people with active tb have robust th1 responses, indicating that these are not sufficient to protect against disease. recent findings suggest that favourable outcomes following mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. we hypothesised that h ...201626986567
proficient detection of multi-drug-resistant mycobacterium tuberculosis by padlock probes and lateral flow nucleic acid biosensors.tuberculosis is a major communicable disease. its causative agent, mycobacterium tuberculosis, becomes resistant to antibiotics by acquisition of point mutations in the chromosome. multi-drug-resistant tuberculosis (mdr-tb) is an increasing public health threat, and prompt detection of such strains is of critical importance. as rolling circle amplification of padlock probes can be used to robustly distinguish single-nucleotide variants, we combined this technique with a sensitive lateral flow nu ...201626985774
2-(quinolin-4-yloxy)acetamides are active against drug-susceptible and drug-resistant mycobacterium tuberculosis strains.2-(quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of mycobacterium tuberculosis growth. herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (mic) values as low as 0.05 μm. further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to vero and hacat cells (ic50s ≥ 20 μm). in addition, the 2-(quinolin-4-y ...201626985307
laboratory diagnosis of mycobacterium tuberculosis infection and disease in children.diagnosis of tuberculosis in children is challenging; even with advanced technologies, the diagnosis is often difficult to confirm microbiologically in part due to the paucibacillary nature of the disease. clinical diagnosis lacks standardization, and traditional and molecular microbiologic methods lack sensitivity, particularly in children. immunodiagnostic tests may improve sensitivity, but these tests cannot distinguish tuberculosis disease from latent infection and some lack specificity. whi ...201626984977
the m. tuberculosis had phosphatase (rv3042c) interacts with host proteins and is inhibited by clofazimine.mycobacterium tuberculosis codes for a had-phosphatase, rv3042c (mtserb2), that has earlier been characterized as a metabolic enzyme. here we demonstrate that mtserb2 is secreted into the cytosol of infected macrophages and is found in bronchoalveolar lavage samples of tuberculosis patients. mtserb2 induces significant cytoskeleton rearrangements through cofilin activation and affects the expression of genes that regulate actin dynamics. it specifically interacts with hsp90, hsp70 and hsp27 that ...201626984196
adjunctive phosphodiesterase-4 inhibitor therapy improves antibiotic response to pulmonary tuberculosis in a rabbit model.adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (tb). we tested the ability of a phosphodiesterase-4 inhibitor (pde4i) cc-11050, co-administered with the first-line anti-tb drug isoniazid (inh), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental mycobacterium tuberculosis (mtb) infection.201626981575
molecular typing characteristic and drug susceptibility analysis of mycobacterium tuberculosis isolates from zigong, china.china is one of the 22 countries with high tb burden worldwide, and sichuan contained the second-largest number of tb cases among all of the chinese provinces. but the characteristics of mycobacterium tuberculosis circulated in zigong, sichuan, were still unknown. to investigate the character and drug resistance profile, 265 clinical isolates were cultured from tuberculosis patient's sputum samples in the year of 2010, of which the genetic profile was determined by using spoligotyping and miru-v ...201626981535
genome sequencing and annotation of multidrug resistant mycobacterium tuberculosis (mdr-tb) pr10 strain.here, we report the draft genome sequence and annotation of a multidrug resistant mycobacterium tuberculosis strain pr10 (mdr-tb pr10) isolated from a patient diagnosed with tuberculosis. the size of the draft genome mdr-tb pr10 is 4.34 mbp with 65.6% of g + c content and consists of 4637 predicted genes. the determinants were categorized by rast into 400 subsystems with 4286 coding sequences and 50 rnas. the whole genome shotgun project has been deposited at ddbj/embl/genbank under the accessio ...201626981419
genome sequencing and annotation of mycobacterium tuberculosis pr08 strain.mycobacterium tuberculosis is an acid fast bacterial species in the family mycobacteriaceae and is the causative agent of most cases of tuberculosis. here, we report the genomic features of mycobacterium tuberculosis isolated from the cerebrospinal fluid (csf) of a patient diagnosed with both pulmonary and extrapulmonary tuberculosis (tb). the isolated strain was identified as mycobacterium tuberculosis pr08 (mtb pr08). genomic dna of the mtb pr08 strain was extracted and subjected to whole geno ...201626981383
drug resistance pattern of mycobacterium tuberculosis isolates from patients referred to tb reference laboratory in ahvaz.tuberculosis remains one of the top three infectious disease killers. the prevalence of multidrug-resistant tuberculosis (mdr-tb) has increased substantially in the past 20 years. when drug resistance is not detected, mdr-tb patients cannot access life-saving treatment; this puts their communities at risk of ongoing mdr-tb transmission. we aimed to determine the patterns of resistance to antituberculosis drugs among mycobacterium tuberculosis isolates from khuzestan province in iran.201626981340
inhibition of mycobacterium-rmla by molecular modeling, dynamics simulation, and docking.the increasing resistance to anti-tb drugs has enforced strategies for finding new drug targets against mycobacterium tuberculosis (mtb). in recent years enzymes associated with the rhamnose pathway in mtb have attracted attention as drug targets. the present work is on α-d-glucose-1-phosphate thymidylyltransferase (rmla), the first enzyme involved in the biosynthesis of l-rhamnose, of mtb cell wall. this study aims to derive a 3d structure of rmla by using a comparative modeling approach. struc ...201626981117
profiling the human immune response to mycobacterium tuberculosis by human cytokine array.tuberculosis (tb) continues to be one of the most serious infectious diseases in the world, however, no effective biomarkers can be used for rapid screening of latent tuberculosis infection (ltbi) and active tb. in this study, serum cytokines were screened and tested as potential biomarker for tb diagnosis.201626980502
dynamics of the t cell response to mycobacterium tuberculosis dosr and rpf antigens in a colombian population of household contacts of recently diagnosed pulmonary tuberculosis patients.immune response to dosr and rpf antigens from mycobacterium tuberculosis (mtb) seems to be important for latency maintenance. little is known about the dynamics of the immune response to these antigens in an endemic community. thus, the ifnγ response and cytokine production in response to ppd, esat6-cfp10 (e6-c10), dosr and rpf antigens in healthy hhc of tuberculosis (tb) patients over a 12 (t12) months period (short-term, stltbi) was investigated. this response was compared with a group of ltbi ...201626980501
canonical pathways, networks and transcriptional factor regulation by clinical strains of mycobacterium tuberculosis in pulmonary alveolar epithelial cells.limited knowledge exists on pathways, networks and transcriptional factors regulated within epithelial cells by diverse mycobacterium tuberculosis genotypes. this study aimed to elucidate these mechanisms induced in a549 epithelial cells by dominant clinical strains in kwazulu-natal, south africa. rna for sequencing was extracted from epithelial cells at 48 h post-infection with 5 strains at a multiplicity of infection of approximately 10:1. bioinformatics analysis performed with the rna-seq tux ...201626980499
morphological changes and differentially expressed efflux pump genes in mycobacterium tuberculosis exposed to a rifampicin and verapamil combination.the aim of the present study was to (i) evaluate the in vitro action of rifampicin (rif), ethambutol or isoniazid with efflux pumps inhibitors (epis) in mycobacterium tuberculosis (mtb) h37rv and (ii) evaluate the morphological and efflux pumps (eps) transcriptional changes by the action of rifampicin + verapamil combination (rif + vp). the minimal inhibitory concentration and synergic effect of drug combinations were determined by resazurin microtiter plate assay and resazurin drugs combination ...201626980498
first insight into the molecular epidemiology of mycobacterium tuberculosis in santa catarina, southern brazil.molecular epidemiology of mycobacterium tuberculosis is useful for understanding disease transmission dynamics, and to establish strategic measures for tb control and prevention. the aim of this study was to analyze clinical, epidemiological and molecular characteristics of mtbc clinical isolates from santa catarina state, southern brazil. during one-year period, 406 clinical isolates of mtbc were collected from central laboratory of public health and typed by spoligotyping. demographic and clin ...201626980497
mutations in lysx as the new and reliable markers for tuberculosis beijing and modern beijing strains.genotyping results and dna sequencing analysis of 235 mycobacterium tuberculosis (m. tuberculosis) isolates from china indicated that mutations at codon 995 (pro ccg to pro cca) and 701 (ile att to thr act) in lysx gene (rv1640c), are specific markers for beijing and modern beijing strains, respectively. this observation was also confirmed by 24 genomes of m. tuberculosis strains from other countries. moreover, a simple and fast multiplex allele-specific pcr (mas-pcr) method for detecting mutati ...201626980493
evaluation of a lens-free imager to facilitate tuberculosis diagnostics in mods.tuberculosis (tb) control efforts are hampered by a mismatch in diagnostic technology. lack of adequate early diagnostics and multi-drug resistant (mdr) detection is a critical problem in control efforts. alternate and novel diagnostic approaches are required, especially in low-resources settings where they are needed most. the microscopic observation drug susceptibility (mods) assay is a cost-effective, highly sensitive, and specific method based on the detection of characteristic cording growt ...201626980492
comparison of the socio-demographic and clinical features of pulmonary tb patients infected with sub-lineages within the w-beijing and non-beijing mycobacterium tuberculosis.highly lethal outbreaks of multidrug-resistant (mdr) and extensively drug-resistant (xdr) tuberculosis are increasing. mycobacterium tuberculosis variant beijing family and its members is regarded as a successful clone of m. tuberculosis that is associated with drug resistance in china. understanding the genetic characteristics and molecular mechanism of drug resistant tuberculosis within beijing family may help to clarify its origin and evolutionary history and the driving forces behind its eme ...201626980491
mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism.survival of mycobacterium tuberculosis (mtb) within the host macrophage is mediated through pathogen-dependent inhibition of phagosome-lysosome fusion, which enables bacteria to persist within the immature phagosomal compartment. by employing ultrastructural examination of different field isolates supported by biochemical analysis, we found that some of the mtb strains were in fact poorly adapted for subsistence within endocytic vesicles of infected macrophages. instead, through a mechanism invo ...201626980157
primary nasopharyngeal tuberculosis: a case report.the occurrence of nasopharyngeal tuberculosis is rare even in areas where tuberculosis is endemic. here, we report a case of rare primary nasopharyngeal tuberculosis, promptly evaluated by nasolaryngoscopy.201626980081
the plasmid-mediated evolution of the mycobacterial esx (type vii) secretion systems.the genome of mycobacterium tuberculosis contains five copies of the esx gene cluster, each encoding a dedicated protein secretion system. these esx secretion systems have been defined as a novel type vii secretion machinery, responsible for the secretion of proteins across the characteristic outer mycomembrane of the mycobacteria. some of these secretion systems are involved in virulence and survival in m. tuberculosis; however they are also present in other non-pathogenic mycobacteria, and hav ...201626979252
mic of delamanid (opc-67683) against mycobacterium tuberculosis clinical isolates and a proposed critical concentration.the increasing global burden of multidrug-resistant tuberculosis (mdr-tb) requires reliable drug susceptibility testing that accurately characterizes susceptibility and resistance of pathogenic bacteria to effectively treat patients with this deadly disease. delamanid is an anti-tb agent first approved in the european union in 2014 for the treatment of pulmonary mdr-tb in adults. using the agar proportion method, delamanid mic was determined for 460 isolates: 316 from patients enrolled in a phas ...201626976868
multiscale model of mycobacterium tuberculosis infection maps metabolite and gene perturbations to granuloma sterilization predictions.granulomas are a hallmark of tuberculosis. inside granulomas, the pathogen mycobacterium tuberculosis may enter a metabolically inactive state that is less susceptible to antibiotics. understanding m. tuberculosis metabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. two key adaptations of m. tuberculosis are a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic cond ...201626975995
the etiology, clinical presentation and long-term outcome of spondylodiscitis in children.spondylodiscitis (sd) is a rare disease in children and diagnosis can be delayed because of the scarcity in incidence and lack of awareness. the purpose of this study was to evaluate and report the microbiologic epidemiology and clinical features of pediatric sd in south korea.201626974751
antituberculosis activity of a naturally occurring flavonoid, isorhamnetin.isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti-inflammatory properties. the present study demonstrated that 1 had antimycobacterial effects on mycobacterium tuberculosis h37rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 μm, respectively. mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. we investigated the ...201626974691
combined genotypic, phylogenetic, and epidemiologic analyses of mycobacterium tuberculosis genetic diversity in the rhône alpes region, france.the present work relates to identification and a deep molecular characterization of circulating mycobacterium tuberculosis complex (mtbc) strains in the rhône-alpes region, france from 2000 to 2010. it aimed to provide with a first snapshot of mtbc genetic diversity in conjunction with bacterial drug resistance, type of disease and available demographic and epidemiologic characteristics over an eleven-year period, in the south-east of france.201627128522
discriminating unalike single nucleobase mismatches using a molecularly resolved, label-free, interfacial lna-based assay.a number of reports have been made in recent times on label-free detection of nucleic acid sequences. however, most of these studies deal with ensemble measurements, therefore lacking in molecular level resolution. these assays have usually employed ssdna sensor probes, and often suffered from problems of irreproducibility and poor sequence-selectivity. herein, the applicability of surface-anchored single stranded locked nucleic acid (sslna) probes has been assessed in the detection of target dn ...201627124266
the usefulness of serum cxcr3 ligands for evaluating the early treatment response in tuberculosis: a longitudinal cohort study.cell-mediated immunity plays an important role in the pathobiology of tuberculosis (tb). the ligands for cxc chemokine receptor 3 (cxcr3) activate the t-helper type 1 lymphocyte pathway. the cxcr3 ligands are reportedly useful clinical markers for the diagnosis and follow-up of tb. the objective of this study was to assess the utility of cxcr3 ligands for evaluating early treatment responses in tb.we recruited 88 patients who underwent antituberculous chemotherapy. the serum levels of interferon ...201627124069
evaluation of the immune response to interferon gamma release assay and tuberculin skin test among bcg vaccinated children in east of egypt: a cross-sectional study.bacille calmette-guérin vaccine (bcg) vaccination is used routinely in most of countries, especially developing one. the efficacy of the bcg vaccination generally decreases with time. the tuberculin skin test (tst) is a most popular diagnostic test for suspicion of tuberculosis (tb) in children till now, but it has many false positives. the interferon-gamma release assay (igra) is more specific than tst for detection of childhood tb, as it is more specific to mycobacterium tuberculosis.evaluate ...201627124042
25-hydroxy vitamin d, vitamin d receptor and toll-like receptor 2 polymorphisms in spinal tuberculosis: a case-control study.vitamin d deficiency and vitamin d receptor (vdr) gene abnormalities confer susceptibility to tuberculosis. toll-like receptors (tlrs), such astlr-2, are also important mediators of inflammatory response against mycobacterium tuberculosis. we evaluated serum vitamin d, and vdr and tlr-2 gene polymorphisms in patients with spinal tuberculosis.this study comprised of 3 groups: spinal tuberculosis, pulmonary tuberculosis, and controls (each with 106 subjects). enzyme-linked immunosorbent assay was ...201627124026
the role of pcr in diagnosis of a rare appendicular tuberculosis and mini literature review.tuberculosis is a prevalent public health problem especially in the poor developing countries and results in significant mortality. albeit tuberculosis almost always affects any organ or system of the body, abdominal tuberculosis is less frequent; moreover, tuberculous appendicitis is very rare with an incidence estimated at about 0.1-0.6% of all gastrointestinal tuberculosis. the purpose of this report was to present an unusual case of primary tuberculous appendicitis and the approach used for ...201627123348
physiology, biochemistry, and applications of f420- and fo-dependent redox reactions.5-deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. while structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of n-5 of the isoalloxazine ring for a carbon. 8-hydroxy-5-deazaflavin (fo) appears to be used for a single function: as a light-harvesting chromophore for dna photolyases across t ...201627122598
bcg and new preventive tuberculosis vaccines: implications for healthcare workers.healthcare workers (hcws) are at high risk of mycobacterium tuberculosis (mtb) infection and tuberculosis disease, but also play a crucial role in implementing healthcare. preexposure tuberculosis vaccination, including revaccination with bcg, might benefit mtb-uninfected hcws, but most hcws in tuberculosis-endemic countries are already sensitized to mycobacteria. a new postexposure tuberculosis vaccine offers greatest potential for protection, in the setting of repeated occupational mtb exposur ...201627118856
unnatural amino acid analogues of membrane-active helical peptides with anti-mycobacterial activity and improved stability.the emergence of mdr-tb, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. we therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities.201627118774
resistance of mycobacterium tuberculosis to daptomycin. 201627117762
development of a web-based tool for automated processing and cataloging of a unique combinatorial drug screen.facing totally resistant bacteria, traditional drug discovery efforts have proven to be of limited use in replenishing our depleted arsenal of therapeutic antibiotics. recently, the natural anti-bacterial properties of metal ions in synergy with metal-coordinating ligands have shown potential for generating new molecule candidates with potential therapeutic downstream applications. we recently developed a novel combinatorial screening approach to identify compounds with copper-dependent anti-bac ...201627117032
genetic signatures of mycobacterium tuberculosis nonthaburi genotype revealed by whole genome analysis of isolates from tuberculous meningitis patients in thailand.genome sequencing plays a key role in understanding the genetic diversity of mycobacterium tuberculosis (m.tb). the genotype-specific character of m. tb contributes to tuberculosis severity and emergence of drug resistance. strains of m. tb complex can be classified into seven lineages. the nonthaburi (nb) genotype, belonging to the indo-oceanic lineage (lineage 1), has a unique spoligotype and is6110-rflp pattern but has not previously undergone a detailed whole genome analysis. in addition, th ...201627114869
immune activation of the host cell induces drug tolerance in mycobacterium tuberculosis both in vitro and in vivo.successful chemotherapy against mycobacterium tuberculosis (mtb) must eradicate the bacterium within the context of its host cell. however, our understanding of the impact of this environment on antimycobacterial drug action remains incomplete. intriguingly, we find that mtb in myeloid cells isolated from the lungs of experimentally infected mice exhibit tolerance to both isoniazid and rifampin to a degree proportional to the activation status of the host cells. these data are confirmed by in vi ...201627114608
compnet: a gui based tool for comparison of multiple biological interaction networks.network visualization and analysis tools aid in better understanding of complex biological systems. furthermore, to understand the differences in behaviour of system(s) under various environmental conditions (e.g. stress, infection), comparing multiple networks becomes necessary. such comparisons between multiple networks may help in asserting causation and in identifying key components of the studied biological system(s). although many available network comparison methods exist, which employ te ...201627112575
characteristics and treatment outcomes of retreatment tuberculosis patients in benin.objective. to determine among retreatment tuberculosis patients in benin baseline characteristics, culture, and drug sensitivity testing (dst) results and treatment outcomes. materials and methods. a retrospective national cohort study of all retreatment tuberculosis patients in benin in 2013 using registers and treatment cards. results. of 3957 patients with tuberculosis, 241 (6%) were retreatment cases. compared to new pulmonary bacteriologically confirmed tuberculosis (npbct) patients, there ...201627110400
thiol reductive stress induces cellulose-anchored biofilm formation in mycobacterium tuberculosis.mycobacterium tuberculosis (mtb) forms biofilms harbouring antibiotic-tolerant bacilli in vitro, but the factors that induce biofilm formation and the nature of the extracellular material that holds the cells together are poorly understood. here we show that intracellular thiol reductive stress (trs) induces formation of mtb biofilms in vitro, which harbour drug-tolerant but metabolically active bacteria with unchanged levels of atp/adp, nad(+)/nadh and nadp(+)/nadph. the development of these bi ...201627109928
hiv-tb co-infection: mechanisms that drive reactivation of mycobacterium tuberculosis in hiv infection.hiv infection predisposes the host to tuberculosis by impairing the hosts' immune system principally by killing and altering cd4 t-cell function. how hiv infection disrupts cd4 t-cell function, which specifically compromises host immunity to mycobacterium tuberculosis, is poorly understood and is a critical roadblock in developing better vaccine- or immune-based strategies to control and monitor tb in hiv-infected subjects. this review considers key pathways that are altered in hiv-infected subj ...201627109273
tb-hiv co-infection: a catastrophic comradeship.the symbiotic association of tuberculosis (tb) and hiv poses a challenge to human survival. hiv complicates every aspect of tb including presentation, diagnosis and treatment. hiv-tb patients encounter unique problems like drug-drug interactions, cumulative toxicity, immune reconstitution inflammatory syndrome (iris), lower plasma drug levels and emergence of drug resistance during treatment despite adherence. tb may also be overdiagnosed in hiv due to a number of diseases that closely resemble ...201627109272
potential and development of inhaled rnai therapeutics for the treatment of pulmonary tuberculosis.tuberculosis (tb), caused by the infection of mycobacterium tuberculosis (mtb), continues to pose a serious threat to public health, and the situation is worsening with the rapid emergence of multidrug resistant (mdr) tb. current tb regimens require long duration of treatment, and their toxic side effects often lead to poor adherence and low success rates. there is an urgent need for shorter and more effective treatment for tb. in recent years, rna interference (rnai) has become a powerful tool ...201627108702
tuberculosis: occupational risk among dental healthcare workers and risk for infection among dental patients. a meta-narrative review.tuberculosis transmission among healthcare workers (hcws) and patients is due to the level of mycobacterium tuberculosis (mt) circulation in the community and in the healthcare settings where hcws are active. in contrast, most papers about dentistry report that dental hcws (dhcws) and patients are at relatively high risk, mainly based on tuberculosis case series that occurred in the 80's-90's. this meta-narrative review was designed to evaluate the tuberculosis risk in dentistry accounting for t ...201627106547
evaluation of three real-time pcr assays for differential identification of mycobacterium tuberculosis complex and nontuberculous mycobacteria species in liquid culture media.we evaluated the analytical performance of m. tuberculosis complex (mtbc)/nontuberculous mycobacteria (ntm) pcr assays for differential identification of mtbc and ntm using culture-positive liquid media. eighty-five type strains and 100 consecutive mycobacterial liquid media cultures (mgit 960 system) were analyzed by a conventional pcr assay (mtb-id(®) v3) and three real-time pcr assays (advansure™ tb/ntm real-time pcr, advansure; genedia(®) mtb/ntm detection kit, genedia; real-q mtb & ntm kit, ...201627105774
outbreak of tuberculosis in a closed setting: views on transmission based on results from molecular and conventional methods.this study describes an outbreak of tuberculosis (tb) in a nursing home for men with mental disorders where residency is lengthy or permanent. this type of setting can provide a model of transmission as contact with the rest of society is extremely limited.201627105749
phosphate responsive regulation provides insights for esx-5 function in mycobacterium tuberculosis.pathogenic microbes commonly respond to environmental cues in the host by activating specialized protein secretion systems. mycobacterium tuberculosis uses the specialized type vii esx protein secretion systems to transport a subset of effector proteins. the esx-5 secretion system is involved in virulence, but both the mechanism of regulation and activating signal were unknown. our work, reviewed here, has established that the phosphate sensing pst/senx3-regx3 system directly activates esx-5 sec ...201627105642
a case of disseminated multidrug-resistant tuberculosis involving the brain.we report a case of a 23-year-old female immigrant from china who was diagnosed with multidrug-resistant tuberculosis affecting her lung and brain, resistant to the standard first-line therapeutics and streptomycin. she was treated with prothionamide, moxifloxacin, cycloserine, and kanamycin. however, her headache and brain lesion worsened. after the brain biopsy, the patient was confirmed with intracranial tuberculoma. linezolid was added to intensify the treatment regimen, and steroid was adde ...201627104015
fret reveals multiple interaction states between two component signalling system proteins of m. tuberculosis.two component signalling involves interaction between sensor kinase (sk) and response regulator (rr) proteins which depends on their phosphorylation status.201627102281
click-based synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene-1,2,3-triazoles with piperidine, piperazine, morpholine and thiomorpholine appendages.a series of novel piperidine, piperazine, morpholine and thiomorpholine appended dibenzo[b,d]thiophene-1,2,3-triazoles were designed and synthesized utilizing azide-alkyne click chemistry in the penultimate step. the required azide building block 6a-e was synthesized from commercial dibenzo[b,d]thiophene in good yields following five step reaction sequence. all the new analogues 8a-f, 9a-f, 10a-f, 11a-f &12a-f were characterized by their nmr and mass spectral analysis. screening all thirty new c ...201627101894
crystal structures of the transpeptidase domain of the mycobacterium tuberculosis penicillin-binding protein pona1 reveal potential mechanisms of antibiotic resistance.mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. the rapid global spread of antibiotic-resistant m. tuberculosis makes tuberculosis infections difficult to treat. to overcome this problem new effective antimicrobial strategies are urgently needed. one promising target for new therapeutic approaches is pona1, a class a penicillin-binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth ...201627101811
inflammasome genetics contributes to the development and control of active pulmonary tuberculosis.tuberculosis (tb) continues to be a major public health problem. an estimated one-third of the world's population is infected with mycobacterium tuberculosis (mtb) but remains asymptomatic (latent tb) and only 5% to 10% of these latent individuals will develop active pulmonary tb. factors affecting the balance between latent and active tb are mostly unknown, even if host genome has been shown to contribute to the outcome of mtb response. acute inflammation and th1 response are important in the e ...201627101784
novel anthra[1,2-c][1,2,5]thiadiazole-6,11-diones as promising anticancer lead compounds: biological evaluation, characterization & molecular targets determination.the novel compounds nsc745885 and nsc757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the national cancer institute, usa, and a panel of 39 cancer cell lines at the japanese foundation of cancer research. both compounds demonstrated selective unique multi-log differential patterns of activity, with gi50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. nsc757963 showed high selectivity towards the leukemia subpanel ...201627100886
total chemical synthesis of lassomycin and lassomycin-amide.herein we report a practical synthetic route to the lasso peptide lassomycin () and c-terminal variant lassomycin-amide (). the biological evaluation of peptides and against mycobacterium tuberculosis revealed that neither had any activity against this bacterium. this lack of biological activity has led us to propose that naturally occurring lassomycin may actually exhibit a standard lasso peptide threaded conformation rather than the previously reported unthreaded structure.201627101411
nontuberculous mycobacteria isolated from tuberculosis suspects in ibadan, nigeria.in nigeria, one of the highest tuberculosis (tb) burdened nations, sputum smear microscopy is routinely employed for tb diagnosis at directly observed treatment short-course (dots) centers. this diagnostic algorithm does not differentiate mycobacterium tuberculosis complex (mtc) from nontuberculous mycobacteria (ntm). between december 2008 and january 2009, consecutive patients diagnosed with tb were screened for inclusion at 10 dots centers in ibadan, nigeria. to verify mycobacterium species in ...201627099795
gene xpert for direct detection of mycobacterium tuberculosis in stool specimens from children with presumptive pulmonary tuberculosis.gene xpert(gx) is a novel real time polymerase chain reaction (rt-pcr) assay which was endorsed by the world health organization (who) in 2011 for tuberculosis (tb) diagnosis and susceptibility to refampicin(rif).201627098628
field evaluation of a novel preservation medium to transport sputum specimens for molecular detection of mycobacterium tuberculosis in a rural african setting.to assess the performance of an innovative method of transporting sputum to centralised facilities for molecular detection of mycobacterium tuberculosis: using a swab to inoculate sputum in a transport medium, primestore(®) molecular transport medium (ps-mtm).201627098085
triazolophthalazines: easily accessible compounds with potent antitubercular activity.tuberculosis (tb) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant tb. herein we explored the potential of an alternative class of molecules as anti-tb agents. thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. four of the synthesized compounds w ...201627097919
mycobacterium tuberculosis uganda ii is more susceptible to rifampicin and isoniazid compared to beijing and delhi/cas families.mycobacterium tuberculosis uganda family is the predominant cause of tuberculosis in uganda. reasons for this are not clear but are likely to be due to the rampant person-to-person transmission or delayed susceptibility of the organism to drugs during treatment, which may lead to continuous shedding of infectious bacilli, among others. the objective of this study was to determine in vitro, the susceptibility patterns of m. tuberculosis uganda family compared with beijing and delhi/cas, other m. ...201627097724
mycobacterium tuberculosis rv3628 drives th1-type t cell immunity via tlr2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent beijing k strain.identification of vaccine target antigens (ags) that induce ag-specific th1 immunity is the first step toward the development of a tuberculosis vaccine. here, we evaluated the mycobacterium tuberculosis (mtb) protein rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (dcs). rv3628 activated dcs, increasing their expression of cell surface molecules and augmenting their production of tnf-α, il-1β, il-6, ...201627097115
discordance across phenotypic and molecular methods for drug susceptibility testing of drug-resistant mycobacterium tuberculosis isolates in a low tb incidence country.with increasing incidence of multidrug-resistant tuberculosis (mdr-tb), accurate drug susceptibility testing (dst) of mycobacterium tuberculosis to first-line drugs has become crucial for proper patient management. we evaluated concordance of dst results for 70 m. tuberculosis isolates across two phenotypic and two molecular methods: bactec 460tb, mgit 960 system, genotype mtbdrplus and dna sequencing of gene segments most commonly implicated in conferring resistance to anti-tb drugs. most (84%) ...201627096759
a web-based platform for designing vaccines against existing and emerging strains of mycobacterium tuberculosis.development of an effective vaccine against drug-resistant mycobacterium tuberculosis (mtb) is crucial for saving millions of premature deaths every year due to tuberculosis. this paper describes a web portal developed for assisting researchers in designing vaccines against emerging mtb strains using traditional and modern approaches. firstly, we annotated 59 genomes of mycobacterium species to understand similarity/dissimilarity between tuberculoid, non-tuberculoid and vaccine strains at genome ...201627096425
preparation and preclinical evaluation of inhalable particles containing rapamycin and anti-tuberculosis agents for induction of autophagy.mycobacterium tuberculosis (mtb) inhibits host defense mechanisms, including autophagy. we investigated particles containing rapamycin (rap) alone or in combination with isoniazid (inh) and rifabutin (rfb) for: targeting lung macrophages on inhalation; inducing autophagy; and killing macrophage-resident mtb and/or augmenting anti-tuberculosis (tb) drugs.201627095353
corrigendum: rapid antibiotic-resistance predictions from genome sequence data for staphylococcus aureus and mycobacterium tuberculosis. 201627095245
a putative nitroreductase from the dosr regulon of mycobacterium tuberculosis induces pro-inflammatory cytokine expression via tlr2 signaling pathway.tuberculosis caused by mycobacterium tuberculosis is a global encumbrance and it is estimated that nearly one third population of the world acts as a reservoir for this pathogen without any symptoms. in this study, we attempted to characterise one of the genes of dosr regulon, rv3131, a fmn binding nitroreductase domain containing protein, for its ability to alter cytokine profile, an essential feature of m. tuberculosis latency. recombinant rv3131 stimulated pro-inflammatory cytokines in thp-1 ...201627094446
spatiotemporal clustering of mycobacterium tuberculosis complex genotypes in florida: genetic diversity segregated by country of birth.tuberculosis (tb) is caused by members of the mycobacterium tuberculosis complex (mtbc). although the mtbc is highly clonal, between-strain genetic diversity has been observed. in low tb incidence settings, immigration may facilitate the importation of mtbc strains with a potential to complicate tb control efforts.201627093156
correction for bai et al., structural analysis of the dodecameric proteasome activator pafe in mycobacterium tuberculosis. 201627091971
phospholipid-based pyrazinamide spray-dried inhalable powders for treating tuberculosis.sterilization of necrotic granulomas containing mycobacterium tuberculosis is difficult by oral and parenteral drug delivery of antitubercular drugs. pulmonary delivery of these drugs should increase the concentration of drug in the granulomas and, thereby, improve the sterilization. the current study aimed to develop spray-dried (sd) powders composed of pyrazinamide, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (dppc), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine n-(carbonyl-methoxy poly ...201627091294
frequency and distribution of tuberculosis resistance-associated mutations between mumbai, moldova, and eastern cape.molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (dr-tb). sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. we performed pyrosequencing of seven mycobacterium tuberculosis gene regions (katg, inha, ahpc, rpob, gyra, rrs, and eis) for 1 ...201627090176
mycobacterium tuberculosis induces the mir-33 locus to reprogram autophagy and host lipid metabolism.mycobacterium tuberculosis (mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. we found that by inducing the microrna (mirna) mir-33 and its passenger strand mir-33*, mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. silencing of mir-33 and mir-33* by genetic or pharmacological means promoted autophagy f ...201627089382
synthesis of cpzen-45: construction of the 1,4-diazepin-2-one core by the cu-catalyzed intramolecular amidation of a vinyl iodide.cpzen-45 was developed as an antibiotic against mycobacterium tuberculosis by the chemical modification of caprazamycins. cpzen-45 has been synthesized in this study by the cu-catalyzed intramolecular amidation of a complex vinyl iodide precursor bearing uridine and sugar moieties with a secondary amide, allowing for the construction of its 1,4-diazepin-2-one core.201627088563
a histomorphological pattern analysis of pulmonary tuberculosis in lung autopsy and surgically resected specimens.background. tuberculosis (tb) is a major cause of morbidity and mortality globally. many cases are diagnosed on autopsy and a subset of patients may require surgical intervention either due to the complication or sequelae of tb. materials and methods. 40 cases of resected lung specimens following surgery or autopsy in which a diagnosis of pulmonary tuberculosis was made were included. histopathological pattern analysis of pulmonary tuberculosis along with associated nonneoplastic changes and ide ...201627088035
[analysis on human t cell epitopes polymorphisms of five specific antigens of mycobacterium tuberculosis in 13 areas of china].to investigate the polymorphisms of the coding gene and the human t cell epitopes of antigen glna1, mpt70, lppx, groes and lpqh on mycobacterium tuberculosis complex (mtbc) strains in thirteen provinces of china.201627087225
cytokinin nucleosides - natural compounds with a unique spectrum of biological activities.cytokinin nucleosides exhibit antitumor, antiviral, antiprotozoal, blood pressure reducing, anti-inflammatory, and antipsychotic activity. these compounds also influence platelet aggregation and exhibit some other biological activities. cytokinins are n6-substituted adenines and represent an important group of phytohormones with diverse biochemical functions in plants, stimulating cell division and plant growth. the main structural feature of cytokinin nucleosides is the presence of a hydrophobi ...201627086793
molecular epidemiology of tuberculosis in victoria, australia, reveals low level of transmission.victoria, australia.201627084820
multitargeted loop-mediated isothermal amplification for rapid diagnosis of tuberculous meningitis.rapid and accurate diagnosis of tuberculous meningitis (tbm) is imperative for the optimal management of patients. loop-mediated isothermal amplification (lamp) is a promising nucleic-acid amplification assay, especially for resource-poor, endemic countries.201627084816
manual mgit™ system for the detection of mycobacterium tuberculosis: insights from a high tb burden setting.to evaluate the diagnostic performance of manual mgit™ (mmgit) compared to the gold standard, löwenstein-jensen (lj), in the diagnosis of pulmonary tuberculosis (tb) in a high-burden setting.201627084813
occupational tuberculosis in denmark through 21 years analysed by nationwide genotyping.tuberculosis (tb) is a well-known occupational hazard. based on more than two decades (1992-2012) of centralized nationwide genotyping of all mycobacterium tuberculosis culture-positive tb patients in denmark, we compared m. tuberculosis genotypes from all cases notified as presumed occupational (n = 130) with m. tuberculosis genotypes from all tb cases present in the country (n = 7,127). from 1992 through 2006, the is6110 restriction fragment length polymorphism (rflp) method was used for genot ...201627082745
phylogenetic and structural significance of dihydrofolate synthase (folc) mutations in drug-resistant mycobacterium tuberculosis.the aim of this study is to investigate the mutation pattern of the folc gene in drug-resistant mycobacterium tuberculosis (mtb) clinical isolates of global and hong kong cohorts. the public sequence read archives of 1,124 mtb genomes from three independent studies were retrieved and folc mutations existing solely in drug-resistant mtb strains were identified. a phylogenetic tree was constructed to analyze the segregation of mutation-related amino acid residues in the folc structure. these mutat ...201627082669
infectious diseases perspective of anorectal abscess and fistula-in-ano disease.anorectal abscess and fistula-in-ano is a rare disease with an exemplary prognosis. most patients are diagnosed with cryptoglandular disease but unusual infections raise difficult antimicrobial management challenges.201627079352
structural basis of dna sequence recognition by the response regulator phop in mycobacterium tuberculosis.the transcriptional regulator phop is an essential virulence factor in mycobacterium tuberculosis, and it presents a target for the development of new anti-tuberculosis drugs and attenuated tuberculosis vaccine strains. phop binds to dna as a highly cooperative dimer by recognizing direct repeats of 7-bp motifs with a 4-bp spacer. to elucidate the phop-dna binding mechanism, we determined the crystal structure of the phop-dna complex. the structure revealed a tandem phop dimer that bound to the ...201627079268
mycobacterium tuberculosis eis gene inhibits macrophage autophagy through up-regulation of il-10 by increasing the acetylation of histone h3.autophagy plays a crucial role in the progress of mycobacterium tuberculosis (mtb) infection. recently, mtb enhanced intracellular survival (eis) protein was reported to be secreted from mtb cells and linked to the inhibition of autophagy and the intracellular persistence of the pathogen. here, we investigated the mechanism of eis-mediated inhibition of autophagy in a human phorbol myristate acetate (pma)-treated thp-1 cell line as well as in murine macrophages. we confirmed that the presence of ...201627079235
coinfections in intensive care unit with pulmonary tuberculosis and mucormycosis: a clinical dilemma.herein, we present the case report of an adult male diabetic patient who had coinfection with mycobacterium tuberculosis and mucormycosis, which otherwise is a rare clinical entity. diabetes mellitus may predispose a patient to tuberculosis (tb) infection which further weakens immune system thus making him susceptible to other fungal or bacterial infections which may pose various treatment difficulties. therefore, there is a need for mycological and bacteriological investigations in patients wit ...201627076735
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