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ppar-γ and akt regulate glut1 and glut3 surface localization during mycobacterium tuberculosis infection.the success of mycobacterium tuberculosis (mtb) as a pathogen stems from its ability to manipulate the host macrophage towards increased lipid biogenesis and lipolysis inhibition. inhibition of lipolysis requires augmented uptake of glucose into the host cell causing an upregulation of the glucose transporters glut1 and glut3 on the cell surface. mechanism behind this upregulation of the glut proteins during mtb infection is hitherto unknown and demands intensive investigation in order to unders ...201728852964
mycobacterium tuberculosis major facilitator superfamily transporters.the cell membrane or biofilm serve as permeable barrier for xenobiotics to maintain the homeostasis of cells or bacterial community. transport systems are essential for the uptake of nutrients and substances necessary for biofilm formation, efflux of deleterious compounds, as well as communication between cells and environment. major facilitator superfamily (mfs) represents the largest secondary transporter family and is responsible for the transport of a broad spectrum of substrates with divers ...201728852815
mycobacterium tuberculosis multidrug-resistant strain m induces low il-8 and inhibits tnf-α secretion by bronchial epithelial cells altering neutrophil effector functions.m strain, the most prevalent multidrug-resistant strain of mycobacterium tuberculosis (mtb) in argentina, has mounted mechanisms to evade innate immune response. the role of human bronchial epithelium in mtb infection remains unknown as well as its crosstalk with neutrophils (pmn). in this work, we evaluate whether m and h37rv strains invade and replicate within bronchial epithelial cell line calu-6 and how conditioned media (cm) derived from infected cells alter pmn responses. we demonstrated t ...201728852268
label-free optical vibrational spectroscopy to detect the metabolic state of m. tuberculosis cells at the site of disease.tuberculosis relapse is a barrier to shorter treatment. it is thought that lipid rich cells, phenotypically resistant to antibiotics, may play a major role. most studies investigating relapse use sputum samples although tissue bacteria may play an important role. we developed a non-destructive, label-free technique combining wavelength modulated raman (wmr) spectroscopy and fluorescence detection (nile red staining) to interrogate mycobacterium tuberculosis cell state. this approach could differ ...201728852109
a comprehensive study of interaction between peptidoglycan fragments and extracelluar domain of mycobacterium tuberculosis ser/thr kinase pknb.the mycobacterium tuberculosis ser/thr kinase pknb is implicated in the regulation of bacterial cell growth and cell division. the intracellular kinase function of pknb is thought to be triggered by peptidoglycan (pgn) fragments that are recognized by the extracytoplasmic domain of pknb. the pgn in the cell wall of m. tuberculosis has several unusual modifications including the presence of n-glycolyl groups (in addition to the n-acetyl groups) in the muramic acid residues, and amidation of d-glu ...201728851116
an application of competitive reporter monitored amplification (cma) for rapid detection of single nucleotide polymorphisms (snps).single nucleotide polymorphisms (snps) are essential parameters in molecular diagnostics and can be used for the early detection and clinical prognosis in various diseases. available methods for snp detection are still labor-intensive and require a complex laboratory infrastructure, which are not suitable for the usage in resource-limited settings. thus, there is an urgent need for a simple, reliable and rapid approach. in this paper we modified the previously developed competitive reporter moni ...201728850612
non-invasive lung disease diagnostics from exhaled microdroplets of lung fluid: perspectives and technical challenges.the combination of ultra-sensitive assay techniques and recent improvements in the instrumentation used to collect microdroplets of lung fluid (mlfs) from exhaled breath has enabled the development of noninvasive lung disease diagnostics that are based on mlf analysis. in one example of this approach, electrospun nylon filters were used to collect mlfs from patients with pulmonary tuberculosis. the filters were washed to obtain liquid probes that were then tested for human immunoglobulin a (h-ig ...201728850044
use of digital droplet pcr to detect mycobacterium tuberculosis dna in whole blood-derived dna samples from patients with pulmonary and extrapulmonary tuberculosis.tuberculosis (tb) is a chronic infectious disease that has been threatening public health for many centuries. the clinical diagnostic procedure for tb is time-consuming and laborious. in the last 20 years, real-time fluorescence-based quantitative pcr (real-time pcr) has become a better alternative for tb diagnosis in clinics due to its sensitivity and specificity. recently, digital droplet pcr (ddpcr) has been developed, and it might be an ideal alternative to conventional real-time pcr for mic ...201728848722
abdominal tuberculosis and spontaneous miscarriage.we present a case report of a 23-year-old pakistani woman who had a second trimester spontaneous miscarriage while visiting her family in the kingdom of saudi arabia. a dilatation and curettage (d&c) was done after the miscarriage. she developed sepsis and acute respiratory distress syndrome, requiring intensive care unit admission a few days after the d&c. an exploratory laparotomy was done and she was found to have a pelvic abscess. despite adequate broad spectrum antimicrobial cover, she cont ...201728847990
synthesis and in vitro investigation of halogenated 1,3-bis(4-nitrophenyl)triazenide salts as antitubercular compounds.the diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. in an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. the potency of the series was confirmed against the mycobacterium tuberculosis lab strain h37ra and for the most potent de ...201728845550
integration of metabolomics and transcriptomics reveals a complex diet of mycobacterium tuberculosis during early macrophage infection.nutrient acquisition from the host environment is crucial for the survival of intracellular pathogens, but conceptual and technical challenges limit our knowledge of pathogen diets. to overcome some of these technical roadblocks, we exploited an experimentally accessible model for early infection of human macrophages by mycobacterium tuberculosis, the etiological agent of tuberculosis, to study host-pathogen interactions with a multi-omics approach. we collected metabolomics and complete transcr ...201728845460
phenolic glycolipid facilitates mycobacterial escape from microbicidal tissue-resident macrophages.mycobacterium tuberculosis (mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. we studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. first-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-p ...201728844797
anthranilate phosphoribosyltransferase: binding determinants for 5'-phospho-alpha-d-ribosyl-1'-pyrophosphate (prpp) and the implications for inhibitor design.phosphoribosyltransferases (prts) bind 5'-phospho-α-d-ribosyl-1'-pyrophosphate (prpp) and transfer its phosphoribosyl group (prib) to specific nucleophiles. anthranilate prt (anprt) is a promiscuous prt that can phosphoribosylate both anthranilate and alternative substrates, and is the only example of a type iii prt. comparison of the prpp binding mode in type i, ii and iii prts indicates that anprt does not bind prpp, or nearby metals, in the same conformation as other prts. a structure with a ...201728844746
antioxidant, anti-inflammatory, antiproliferative and antimycobacterial activities of the essential oil of psidium guineense sw. and spathulenol.leaves from psidium guineense sw. are used in popular medicine for the treatment of inflammatory disease. however, there is no scientific evidence demonstrating this activity.201728844678
relation of mycobacterium tuberculosis mutations at katg315 and inha-15 with drug resistance profile, genetic background, and clustering in argentina.we analyzed 362 isoniazid-resistant clinical isolates of mycobacterium tuberculosis obtained countrywide for the presence of mutation at katg315 and inha-15 in relation to genotype, pattern of phenotypic resistance to other drugs, and ability to spread. we found the following mutation frequencies: katg315mut/inha-15wt 53.0%, katg315wt/inha-15mut 27.4%, katg315wt/inha-15wt 19.3%, and katg315mut/inha-15mut only 0.3%. mutation at katg315 associated with the lam superfamily; mutation at inha-15 asso ...201728844342
clofazimine protects against mycobacterium tuberculosis dissemination in the cns following an aerosol challenge in a murine model.tuberculosis (tb) has been the scourge of the human race for many decades, claiming countless number of lives along the way. this is further complicated by the ability of mycobacterium tuberculosis (m.tb) to infect extra-pulmonary sites, more specifically the brain. these forms of tb are difficult to treat due to the problems associated with drug delivery across the blood brain barrier (bbb). linezolid (lzd and clofazimine (cfz) are two of the more promising anti-tb antibiotics in recent times.201728843822
activity of 2-(quinolin-4-yloxy)acetamides in mycobacterium tuberculosis clinical isolates and identification of their molecular target by whole genome sequencing.the 2-(quinolin-4-yloxy)acetamides (qoas) have been reported as promising molecules for tuberculosis treatment. recent studies demonstrated its potent antimycobacterial activity, as well as its biological stability and synergism with rifampicin. the identification of the molecular target is an essential step towards the development of a novel drug candidate. here we report the target identification of the qoas. we found that these compounds are active against isoniazid, rifampicin, ethambutol, s ...201728843821
specific immune responses in mice following subchronic exposure to acetamiprid.acetamiprid (ace) is an insecticide of the neonicotinoid family, the most widely used in the world. herein, we assessed the effect of ace on either the humoral or cellular immune responses of rodents. we also evaluated the role of curcumin in the restoration of altered immune responses after ace treatment.201728843496
inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.drug discovery efforts against the pathogen mycobacterium tuberculosis (mtb) have been advanced through phenotypic screens of extensive compound libraries. such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of mtb infection. here we identify the target and mode of inhibition of these compounds based on whole genome sequenci ...201728842600
structural basis of the pe-ppe protein interaction in mycobacterium tuberculosis.mycobacterium tuberculosis (mtb), the causative agent of tuberculosis, has developed multiple strategies to adapt to the human host. the five type vii secretion systems, esx-1-5, direct the export of many virulence-promoting protein effectors across the complex mycobacterial cell wall. one class of esx substrates is the pe/ppe family of proteins, which is unique to mycobacteria and essential for infection, antigenic variation and host-pathogen interactions. the genome of mtb encodes 168 pe/ppe p ...201728842489
rapid and visual detection of mycobacterium tuberculosis complex using recombinase polymerase amplification combined with lateral flow strips.to definitively diagnose active pulmonary tuberculosis (tb), mycobacterium tuberculosis complex (mtbc) bacilli must be identified within clinical specimens from patients. in this study, we introduced a rapid and visual detection method of mtbc using recombinase polymerase amplification (rpa) combined with lateral flow (lf) strips. the lf-rpa assay, read results with naked eyes, could detect as few as 5 genome copies of m. tuberculosis h37rv (atcc 27294) per reaction and had no cross-reactions wi ...201728842221
esrra (estrogen related receptor, alpha) is a key coordinator of transcriptional and post-translational activation of autophagy to promote innate host defense.the orphan nuclear receptor essra (estrogen related receptor, alpha) is a key regulator of energy homeostasis and mitochondrial function. macroautophagy/autophagy, an intracellular degradation process, is a critical innate effector against intracellular microbes. here, we demonstrate that esrra is required for the activation of autophagy to promote innate antimicrobial defense against mycobacterial infection. amp-activated protein kinase pathway and sirt1 (sirtuin 1) activation led to induction ...201728841353
an expanding role for environmental microbes in shaping the immune response to infection with mycobacterium tuberculosis. 201728841029
interferon gamma release assay in response to pe35/ppe68 proteins: a promising diagnostic method for diagnosis of latent tuberculosis.tuberculosis control relies on the identification and preventive treatment of people who are latently infected with mycobacterium tuberculosis (mtb). pe/ppe proteins have been reported to elicit cd4 and/or cd8 responses either in the form of whole recombinant proteins or as individual peptides. very few of the pe and ppe proteins have been previously tested for responses in patients with tb and healthy donors. this is the first study to evaluate the interferon gamma release assay (igra) after st ...201728840843
bis-spirochromanones as potent inhibitors of mycobacterium tuberculosis: synthesis and biological evaluation.on the basis of reported antimycobacterial property of chroman-4-one pharmacophore, a series of chemically modified bis-spirochromanones were synthesized starting from 2-hydroxyacetophenone and 1,4-dioxaspiro[4.5] decan-8-one using a kabbe condensation approach. the synthesized bis-spirochromanones were established based on their spectral data and x-ray crystal structure of 6e. all synthesized compounds were evaluated against mycobacterium tuberculosis h37rv (atcc 27294) strain, finding that som ...201728840414
smear grading and the mantoux skin test can be used to predict sputum smear conversion in patients suffering from tuberculosis.purpose: smear scores and induration sizes resulting from the ppd (tuberculin purified protein derivative) test can serve as indicators of whether a patient suffering from tuberculosis shows smear conversion or not. methods: using microbiological methods smear and sputum tests, patients diagnosed as infected with mycobacterium tuberculosis between 2002 and 2015 were included in this study. all of the assumed factors that may have a role in smear conversion were studied, in addition to the prolon ...201728840092
molecular characterisation of isoniazid resistant clinical isolates of mycobacterium tuberculosis from khyber pakhtunkhwa, pakistan.to investigate the frequency of mutations in catalase-peroxidase and inhibin alpha genes in clinical isolates of isoniazid resistant mycobacterium tuberculosis strains.201728839308
correction for arora et al., "respiratory flexibility in response to inhibition of cytochrome c oxidase in mycobacterium tuberculosis". 201728839085
differences in pathogenicity of three animal isolates of mycobacterium species in a mouse model.animal mycobacterioses are among the most important zoonoses worldwide. these are generally caused by either mycobacterium tuberculosis (mtb), m. bovis (mbo) or m. avium (mav). to test the hypothesis that different species of pathogenic mycobacteria isolated from varied anatomic locations or animal species differ in virulence and pathogenicity, we performed experiments with three mycobacteria strains (ntse-3(mtb), ntse-4(mbo) and ntse-5 (mav)) obtained from animal species. spoligotyping analysis ...201728837698
immune characterization of the hbha-specific response in mycobacterium tuberculosis-infected patients with or without hiv infection.rd1-based interferon-γ release assays (igras) cannot distinguish latent from active tuberculosis (tb) disease. conversely, a positive response to heparin-binding haemagglutinin (hbha)-based igras, among tb-infected subjects, correlates with mycobacterium tuberculosis (mtb) containment and low risk of tb progression. the aim of this study was to characterize hbha-immune responses in hiv-infected and uninfected subjects with active tb or latent tb infection (ltbi).201728837654
assessment of the influence of direct tobacco smoke on infection and active tb management.smoking is a risk factor for tuberculosis (tb) infection and disease progression. tobacco smoking increases susceptibility to tb in a variety of ways, one of which is due to a reduction of the ifn-γ response. consequently, an impaired immune response could affect performance of ifn-γ release assays (igras).201728837570
preclinical assessment of a (68)ga-dota-functionalized depsipeptide as a radiodiagnostic infection imaging agent.the study assessed a radiolabeled depsipeptide conjugate ((68)ga-dota-tbia101) for its potential as an imaging agent targeting infection or infection-associated inflammation. (68)ga-labeled dota-tbia101 imaging was performed in (nzr1) healthy rabbits; (nzr2) rabbits bearing muscular sterile inflammation and staphylococcus aureus (sa) infection; and (nzr3) rabbits infected with mycobacterium tuberculosis (mtb) combined with a subcutaneous scruff infection of sa in the same animal. all animals wer ...201728837117
tuberculosis in healthcare workers, scotland.in an attempt to explore healthcare worker acquisition of tuberculosis infection, we conducted population-based surveillance of all cases recorded as healthcare workers reported to enhanced surveillance of mycobacterial infection from 2000 to 2015. over the study period, the mean incidence rate of tuberculosis among all healthcare workers was 15.4 per 100,000 healthcare workers. however, the incidence rate of tuberculosis amongst those healthcare workers born outside the uk was 164.8 per 100,000 ...201728836925
metabolic activity of mature biofilms of mycobacterium tuberculosis and other non-tuberculous mycobacteria.mycobacteria are classified into two groups, fast- and slow-growing. often, fast-growing mycobacteria are assumed to have a higher metabolic activity than their slower counterparts, but in mature biofilms this assumption might not be correct. indeed, when measuring the metabolic activity of mycobacterial biofilms with two independent non-invasive techniques (isothermal microcalorimetry and tunable diode laser absorption spectrometry), mature biofilms of slow- and fast-growing species appeared mo ...201728835629
evolutionary pathway analysis and unified classification of east asian lineage of mycobacterium tuberculosis.due to its rapid spread and association with the numerous outbreaks, the global spread of east asian lineage of mycobacterium tuberculosis strains presents a global concern. although there were many attempts to describe its population structure, no consensus has been reached yet. to define unbiased classification that will facilitate future studies of this lineage, we analyzed the performance and congruence of eight different genotyping schemes based on phylogenetic analysis of 1,398 strains fro ...201728835627
development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents.in this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. we found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. the n-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against mycobacterium tuberculosis cnctc ...201728835350
irak-m alters the polarity of macrophages to facilitate the survival of mycobacterium tuberculosis.intracellular bacterium, mycobacterium tuberculosis (m. tb), infects specifically macrophages as host cells. irak-m, a member of irak family, is a negative regulator in tlr signaling and specifically expresses in monocytes and macrophages. the role of irak-m in intracellular growth of m. tb and macrophage polarization was explored, for deeply understanding the pathogenesis of m. tb, the significance of irak-m to innate immunity and pathogen-host interaction.201728835201
mechanism of the nitric oxide dioxygenase reaction of mycobacterium tuberculosis hemoglobin n.many globins convert •no to innocuous no3(-) through their nitric oxide dioxygenase (nod) activity. mycobacterium tuberculosis fights the oxidative and nitrosative stress imposed by its host (the toxic effects of o2•(-) and •no species and their oono(-) and •no2 derivatives) through the action of truncated hemoglobin n (trhbn), which catalyzes the nod reaction with one of the highest rates among globins. the general nod mechanism comprises the following steps: binding of o2 to the heme, diffusio ...201728835102
total synthesis and mass spectrometric analysis of a mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (r)-tuberculostearic acid.we report the total synthesis of (r)-tuberculostearic acid-containing mycobacterium tuberculosis phosphatidylglycerol (pg). the approach features a two-step synthesis of (r)-tuberculostearic acid, involving an (s)-citronellyl bromide linchpin, and the phosphoramidite-assisted assembly of the full pg structure. collision-induced dissociation mass spectrometry of two chemically-synthesized pg acyl regioisomers revealed diagnostic product ions formed by preferential loss of carboxylate at the secon ...201728831486
new amide and dioxopiperazine derivatives from leaves of breynia nivosa.the first chemical investigation of leaves of breynia nivosa from nigeria resulted in the isolation of two new amide derivatives breynivosamides a and b (1 and 2) and two new dioxopiperazine derivatives breynivosines a and b (4 and 5) together with seven known compounds (3, 6-11). the structures of the new compounds were elucidated by 1d, 2d nmr and hresims data as well as by comparison with the literature. all isolated compounds were tested for the cytotoxic and antimicrobial activities. only c ...201728830789
emergence and clonal transmission of multi-drug-resistant tuberculosis among patients in chad.emergence of multidrug-resistant (mdr) strains constitutes a significant public health problem worldwide. prevalence of mdr tuberculosis from chad is unavailable to date.201728830384
diagnostic utility of a line probe assay for multidrug resistant-tb in smear-negative pulmonary tuberculosis.to evaluate the performance of genotype mtbdrplus ver 2.0 in the diagnosis of mycobacterium tuberculosis (mtb) in sputum smear-negative pulmonary tb cases.201728829779
design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (nad(+)) synthetase inhibitors as potential antitubercular agents.nicotinamide adenine dinucleotide (nad(+)) synthetase catalyzes the last step in nad(+) biosynthesis. depletion of nad(+) is bactericidal for both active and dormant mycobacterium tuberculosis (mtb). by inhibiting nad(+) synthetase (nade) from mtb, we expect to eliminate nad(+) production which will result in cell death in both growing and nonreplicating mtb. nade inhibitors have been investigated against various pathogens, but few have been tested against mtb. here, we report on the expansion o ...201728827112
purinergic signaling: a common path in the macrophage response against mycobacterium tuberculosis and toxoplasma gondii.immune responses are essential for the protection of the host against external dangers or infections and are normally efficient in the clearance of invading microbes. however, some intracellular pathogens have developed strategies to replicate and survive within host cells resulting in latent infection associated with strong inflammation. this excessive response can cause cell and tissue damage and lead to the release of the intracellular content, in particular the nucleotide pool, into the extr ...201728824882
innate immune activation can trigger experimental spondyloarthritis in hla-b27/huβ2m transgenic rats.spondyloarthritis (spa) does not display the typical features of auto-immune disease. despite the strong association with mhc class i, cd8(+) t cells are not required for disease induction in the hla-b27/huβ2m transgenic rats. we used lewis hla-b27/huβ2m transgenic rats [21-3 × 283-2]f1, hla-b7/huβ2m transgenic rats [120-4 × 283-2]f1, and wild-type rats to test our hypothesis that spa may be primarily driven by the innate immune response. in vitro, splenocytes were stimulated with heat-inactivat ...201728824645
bolstering immunity through pattern recognition receptors: a unique approach to control tuberculosis.the global control of tuberculosis (tb) presents a continuous health challenge to mankind. despite having effective drugs, tb still has a devastating impact on human health. contributing reasons include the emergence of drug-resistant strains of mycobacterium tuberculosis (mtb), the aids-pandemic, and the absence of effective vaccines against the disease. indeed, alternative and effective methods of tb treatment and control are urgently needed. one such approach may be to more effectively engage ...201728824632
tuberculosis of the sternoclavicular joint. 201728824083
virtual screening and repositioning of inconclusive molecules of beta-lactamase bioassays-a data mining approach.this study focuses on the best possible way forward in utilizing inconclusive molecules of pubchem bioassays aid 1332, aid 434987 and aid 434955, which are related to beta-lactamase inhibitors of mycobacterium tuberculosis (mtb). the inadequacy in the experimental methods that were observed during the invitro screening resulted in an inconclusive dataset. this could be due to certain moieties present within the molecules. in order to reconsider such molecules, insilico methods can be suggested i ...201728822333
protein kinase g confers survival advantage to mycobacterium tuberculosis during latency like conditions.protein kinase g (pkng), a thioredoxin-fold containing eukaryotic like serine/threonine protein kinase (stpk), is a virulence factor in the mycobacterium tuberculosis, required for inhibition of phago-lysosomal fusion. here, we unravelled novel functional facets of pkng during latency like conditions. we find that pkng mediates persistence under stressful conditions like hypoxia and abets drug tolerance. pkng mutant displayed minimal growth in nutrient limiting conditions suggesting its role in ...201728821621
il-17 production of neutrophils enhances antibacteria ability but promotes arthritis development during mycobacterium tuberculosis infection.to our knowledge, no studies have examined the role of il-17 production by neutrophils in immune defense against mycobacterium tuberculosis (mtb) infection and the pathogenesis of rheumatoid arthritis (ra) caused by mtb infection. here, we determined that neutrophils express il-17 in an autocrine il-6- and il-23-dependent manner during mtb infection. mtb h37rv-induced il-6 production was dependent on the nf-κb, p38, and jnk signaling pathways; however, il-23 production was dependent on nf-κb and ...201728821374
pknb remains an essential and a conserved target for drug development in susceptible and mdr strains of m. tuberculosis.the mycobacterium tuberculosis (m.tb) protein kinase b (pknb) which is now proved to be essential for the growth and survival of m.tb, is a transmembrane protein with a potential to be a good drug target. however it is not known if this target remains conserved in otherwise resistant isolates from clinical origin. the present study describes the conservation analysis of sequences covering the inhibitor binding domain of pknb to assess if it remains conserved in susceptible and resistant clinical ...201728821299
incident mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in brazil.in household contact investigations of tuberculosis (tb), a second tuberculin skin test (tst) obtained several weeks after a first negative result consistently identifies individuals that undergo tst conversion. it remains unclear whether this delay in m. tuberculosis infection is related to differences in the infectious exposure, tst boosting, partial host resistance, or some other factor.201728821234
proteogenomic investigation of strain variation in clinical mycobacterium tuberculosis isolates.mycobacterium tuberculosis consists of a large number of different strains that display unique virulence characteristics. whole-genome sequencing has revealed substantial genetic diversity among clinical m. tuberculosis isolates, and elucidating the phenotypic variation encoded by this genetic diversity will be of utmost importance to fully understand m. tuberculosis biology and pathogenicity. in this study we integrated whole-genome sequencing and mass spectrometry (gelc-ms/ms) to reveal strain ...201728820946
the active site flexibility of mycobacterium tuberculosis isocitrate lyase in dimer form.tuberculosis (tb) still remains as global threat due to the emerging of drug resistant strain. instead of focus on drug target of active stage tb, we are highlighting the isocitrate lyase (icl) at the dormant stage tb. icl is one of the persistent factors for mycobacterium tuberculosis (mtb) to survive during dormant phase. in addition, the absent of icl in human has made icl a potential drug target for tb therapy. however, the dynamics details of icl which could give insights to the icl-ligand ...201728820943
paradoxical worsening of a case of tb subretinal abscess with serpiginous-like choroiditis following the initiation of antitubercular therapy.a 37-year-old immunocompetent male patient presented with the blurring of vision, both eyes for the past1 year. fundus examination revealed bilateral multiple subretinal abscesses with areas of healed serpiginous-like choroiditis. laboratory investigations showed positive tuberculin skin test, positive quantiferon tb-gold test, and high resolution computed tomography chest showed enlarged mediastinal lymph nodes. the aqueous sample revealed polymerase chain reaction (pcr) positive for mycobacter ...201728820170
extensively drug-resistant tuberculosis of the lumbar spine in a six-year-old child: a case report.the emergence of extensively drug-resistant tuberculosis (xdr-tb) is a challenging paradigm shift faced by the tb control programs worldwide today. the treatment is further compounded with unique management difficulties faced in pediatric patients. treatment of xdr-tb requires prolonged chemotherapy with second-line drugs which offer lesser potency and increased risk of drug-related side effects. we present a case of spinal xdr-tb in a child, managed with extended second-line antitubercular chem ...201728819600
multiple jejunal perforation secondary to intestinal tuberculosis infection: a case report.abdominal tuberculosis (tb) may affect any part of the gastrointestinal tract resulting in significant morbidity and mortality. there is an increase in the incidence of abdominal tb favored by the emergence of multi-drug resistant mycobacterium tuberculosis and immunosuppression especially from hiv co-infection. our case is that of a 31 year old hiv-positive woman, adherent to antiretroviral therapy, who presented with a 2 month history of progressive abdominal distention, drenching night sweat ...201728819499
delta inulin-based adjuvants promote the generation of polyfunctional cd4(+) t cell responses and protection against mycobacterium tuberculosis infection.there is an urgent need for the rational design of safe and effective vaccines to protect against chronic bacterial pathogens such as mycobacterium tuberculosis. advax™ is a novel adjuvant based on delta inulin microparticles that enhances immunity with a minimal inflammatory profile and has entered human trials to protect against viral pathogens. in this report we determined if advax displays broad applicability against important human pathogens by assessing protective immunity against infectio ...201728819247
recent advances of pyrazole-containing derivatives as anti-tubercular agents.one-third of the world's population infected tuberculosis (tb), and more than 1 million deaths annually. the co-infection between the mainly pathogen mycobacterium tuberculosis (mtb) and hiv, and the incidence of drug-resistant tb, multi-drug resistant tb, extensively drug-resistant tb as well as totally drug-resistant tb have further aggravated the mortality and spread of this disease. thus, there is an urgent need to develop novel anti-tb agents against both drug-susceptible and drug-resistant ...201728818767
raw starch microparticles have immunostimulant activity in mice vaccinated with bcg and challenged with mycobacterium tuberculosis.the main challenge for vaccine development or improvement is the lack of safe adjuvants or immunostimulants that induce protective immune responses and can be used for mucosal immunization, which is a highly desirable strategy for vaccination against infectious diseases acquired by oral or intranasal routes. one promising alternative is the use of biodegradable and biocompatible polymeric microparticles. recently, we developed an immobilization and delivery system with starch microparticles (smp ...201728818565
experimental study of tuberculosis: from animal models to complex cell systems and organoids.tuberculosis (tb) is a devastating disease to mankind that has killed more people than any other infectious disease. despite many efforts and successes from the scientific and health communities, the prospect of tb elimination remains distant. on the one hand, sustainable public health programs with affordable and broad implementation of anti-tb measures are needed. on the other hand, achieving tb elimination requires critical advances in three areas: vaccination, diagnosis, and treatment. it is ...201728817682
peripheral clinic versus centralized laboratory-based xpert mtb/rif performance: experience gained from a pragmatic, stepped-wedge trial in botswana.in 2011, the botswana national tuberculosis program adopted world health organization guidelines and introduced xpert mtb/rif (xpert) assay to support intensified case finding among people living with hiv enrolling in care. an evaluation was designed to assess performance under operational conditions to inform the national xpert scale-up.201728817643
in vitro antitubercular activity of 3-deoxysappanchalcone isolated from the heartwood of caesalpinia sappan linn.responsible for nearly 1.5 million deaths every year, the infectious disease tuberculosis remains one of the most serious challenges to global health. the emergence of multidrug-resistant tuberculosis and, more recently, extensively drug-resistant tuberculosis poses a significant threat in our effort to control this epidemic. new drugs are urgently needed to combat the growing threat of antimicrobial resistance. to achieve this goal, we screened approximately 500 species of medicinal plant metha ...201728816372
biophysical screening of a focused library for the discovery of cyp121 inhibitors as novel antimycobacterials.the development of novel antimycobacterial agents against mycobacterium tuberculosis (mtb) is urgently required due to the appearance of multi-drug resistance (mdr) combined with a complicated long-term treatment. cyp121 was shown to be a promising novel target for inhibition of mycobacterial growth. in this study, we describe the rational discovery of new cyp121 inhibitors by a systematic screening based on biophysical and microbiological methods. best hits originating from only one structural ...201728815923
determinants of the inhibition of dpre1 and cyp2c9 by antitubercular thiophenes.mycobacterium tuberculosis (mtb) dpre1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (tb) drug development. here we report the x-ray crystal structures of dpre1 and the dpre1 resistant mutant (y314c) in complexes with tca1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. the selected lead compound sho ...201728815830
detection of first-line drug resistance mutations and drug-protein interaction dynamics from tuberculosis patients in south india.diagnosis of drug-resistant tuberculosis predominantly relies on culture-based drug susceptibility testing, which take weeks to produce a result and a more time-efficient alternative method is multiplex allele-specific pcr (mas-pcr). also, understanding the role of mutations in causing resistance helps better drug designing.201728813625
detection of anti-hspx antibodies and hspx protein in patient sera for the identification of recent latent infection by mycobacterium tuberculosis.mycobacterium tuberculosis is a pathogen causing tuberculosis (tb) a spectrum of disease including acute and asymptomatic latent stages. identifying and treating latently-infected patients constitutes one of the most important impediments to tb control efforts. those individuals can remain undiagnosed for decades serving as potential reservoirs for disease reactivation. tests for the accurate diagnosis of latent infection currently are unavailable. hspx protein (α-crystallin), encoded by rv2031c ...201728813434
rauvolfianine, a new antimycobacterial glyceroglycolipid and other constituents from rauvolfia caffra. sond (apocynaceae).the chemical investigation of the extract of the dried leaves of rauvolfia caffra (sond) (synonym rauvolfia macrophylla) (apocynaceae) led to isolation of a new glycoside derivative, rauvolfianine (1) as well as six known compounds: oleanolic acid (2), sitosterol-3-o-β-d-glucopyranoside (3), betulinic acid (4), vellosimine (5), sarpagine (6) and d-fructofuranosyl-β-(2→1)-α-d-glucopyranoside (7). compounds 1, 2, 3, 4 and 7 were evaluated for antitubercular activity. compounds 1 and 2 were the mos ...201728812370
recombinant expression and biochemical characterization of mycobacterium tuberculosis 3fe-4s ferredoxin rv1786.ferredoxins are iron-sulfur protein that mediate electron transfer in cytochrome p450 mono-oxygenase (cyp)-related catalytic reactions in a wide variety of organisms. rv1786 is a putative ferredoxin, encoded by a gene located downstream of the gene encoding cyp143a1 in the mycobacterium tuberculosis genome. however, the structure and function of rv1786 have remained unclear. here, the recombinant mtb rv1786 was expressed, purified as a his-tagged form and characterized with [3fe-4s] clusters as ...201728812125
delayed effects of transcriptional responses in mycobacterium tuberculosis exposed to nitric oxide suggest other mechanisms involved in survival.mycobacterium tuberculosis has succeeded as a human pathogen for tens of thousands of years thanks to its ability to resist and adapt to the adverse conditions it encounters upon infection. bacterial adaptation to stress is commonly viewed in the context of transcriptional regulation, with the implicit expectation that an initial transcriptomic response is tightly coupled to an ensuing proteomic response. however, after challenging m. tuberculosis with nitric oxide we found that the rapid transc ...201728811595
the capacity of mycobacterium tuberculosis to survive iron starvation might enable it to persist in iron-deprived microenvironments of human granulomas.this study was conducted to investigate the role of iron deprivation in the persistence of mycobacterium tuberculosis we present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation m. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. transcriptomics and metabolomic analyses indicated that the persistence of m. tuberculosis under iron starvation is dependent on strict control of endo ...201728811344
outcomes from patients with presumed drug resistant tuberculosis in five reference centers in brazil.the implementation of rapid drug susceptibility testing (dst) is a current global priority for tb control. however, data are scarce on patient-relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pdr-tb) evaluated under field conditions in high burden countries.201728810911
[analysis of infection and drug-resistance in 6 107 cases of extrapulmonary tuberculosis in chengdu area].objective: to analyze the infection and drug resistance of extrapulmonary tuberculosis, in order to provide useful references for prevention and treatment of tuberculosis (tb). methods: a total of 6 107 suspected cases of extrapulmonary tuberculosis, including lymph node, pleural, peritoneal, meningeal, urinary tract, and bone tuberculosis, were collected retrospectively from january 2013 to december 2015 in public health clinical center of chengdu. there were 4 033 male and 2 074 female patient ...201728810312
microencapsulated solid lipid nanoparticles as a hybrid platform for pulmonary antibiotic delivery.solid lipid nanoparticles (sln) containing rifabutin (rfb), with pulmonary administration purposes, were developed through a technique that avoids the use of organic solvents or sonication. to facilitate their pulmonary delivery, the rfb-loaded sln were included in microspheres of appropriate size using suitable excipients (mannitol and trehalose) through a spray-drying technique. confocal analysis microscopy showed that microspheres are spherical and that sln are efficiently microencapsulated a ...201728809501
allium sativum constituents exhibit anti-tubercular activity in vitro and in raw 264.7 mouse macrophage cells infected with mycobacterium tuberculosis h37rv.long duration of treatment, side-effects of currently used anti-tubercular drugs and emergence of drug-resistant forms of mycobacterium tuberculosis (mtb) warrants the need to develop new drugs to tackle the scourge of tuberculosis (tb). garlic is an edible plant reported to have anti-tubercular activity. however, previous researches on anti-tubercular effect of garlic were focused mostly on preliminary in vitro screening.201728808382
assessment of tuberculosis spatial hotspot areas in antananarivo, madagascar, by combining spatial analysis and genotyping.tuberculosis (tb) remains a public health problem in madagascar. a crucial element of tb control is the development of an easy and rapid method for the orientation of tb control strategies in the country. our main objective was to develop a tb spatial hotspot identification method by combining spatial analysis and tb genotyping method in antananarivo.201728806916
new synthetic lipid antigens for rapid serological diagnosis of tuberculosis.during pulmonary tuberculosis (ptb) antibodies are generated to trehalose esters of mycolic acids which are cell wall lipids of mycobacterium tuberculosis (mtb). attempts have been made to use these complex natural mixtures in serological tests for ptb diagnosis.201728806423
linking high-throughput screens to identify moas and novel inhibitors of mycobacterium tuberculosis dihydrofolate reductase.though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (moa) and reveal actionable chemical matter. here, we describe a framework for identifying efficacy targets of bioactive compounds. high throughput biophysical profiling against ...201728806050
a multiple-antigen detection assay for tuberculosis diagnosis based on broadly reactive polyclonal antibodies.detection of circulating mycobacterium tuberculosis (m. tuberculosis) antigens is promising in tuberculosis (tb) diagnosis. however, not a single antigen marker has been found to be widely expressed in all tb patients. this study is aimed to prepare broadly reactive polyclonal antibodies targeting multiple antigen markers (multi-target antibodies) and evaluate their efficacies in tb diagnosis.201728804606
prevalence and treatment outcome of extensively drug-resistant tuberculosis plus additional drug resistance from the national clinical center for tuberculosis in china: a five-year review.the objective of this study was to explore the prevalence and primary clinical outcomes of extensively drug-resistant tuberculosis plus addition resistance to all drug tested (xdr-tb-plus) between 2011 and 2015 in beijing chest hospital.201728804028
the potential of a portable, point-of-care electronic nose to diagnose tuberculosis.tuberculosis (tb) is the leading cause of death due to an infectious disease worldwide. especially in low-income countries, new diagnostic techniques that are accessible, inexpensive and easy-to-use, are needed to shorten transmission time and initiate treatment earlier.201728804027
rifampin vs. rifapentine: what is the preferred rifamycin for tuberculosis?one-third of the world's population is infected with mycobacterium tuberculosis (m.tb.). latent tuberculosis infection (ltbi) can progress to tuberculosis disease, the leading cause of death by infection. rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against m.tb. what are the advantages of each for ltbi or tuberculosis treatment? areas covered: we review studies assessing the pharmacokinetics (pk), pharmacodynamics (pd), drug interaction risk, safety, an ...201728803492
effect of dmso on protein structure and interactions assessed by collision-induced dissociation and unfolding.given the frequent use of dmso in biochemical and biophysical assays, it is desirable to understand the influence of dmso concentration on the dissociation or unfolding behavior of proteins. in this study, the effects of dmso on the structure and interactions of avidin and mycobacterium tuberculosis (mtb) cyp142a1 were assessed through collision-induced dissociation (cid) and collision-induced unfolding (ciu) as monitored by nanoelectrospray ionization-ion mobility-mass spectrometry (nesi-im-ms) ...201728803470
the minipig as an animal model to study mycobacterium tuberculosis infection and natural transmission.in endemic countries more than 20% of tuberculosis (tb) cases are in infants and children. current animal models study tb during adulthood but animal models for infant tb are scarce. here we propose that minipigs can be used as an animal model to study adult, adolescent and infant tb including natural transmission. in these studies, two-month old minipigs (representing infant age in humans) and six-month old minipigs (representing adolescence in humans) were infected via the aerosol route with h ...201728802411
evaluation of 24-locus miru-vntr genotyping in mycobacterium tuberculosis cluster investigations in four jurisdictions in the united states, 2006-2010.the u.s. centers for disease control and prevention (cdc) uses a combination of spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units-variable number of tandem repeats (miru-vntr) analyses as part of the national tb genotyping service (ntgs). the ntgs expansion from 12-locus miru-vntr (miru12) to 24-locus miru-vntr (miru24) in 2009 enhanced the ability to discriminate mycobacterium tuberculosis strains. in the current study, we investigated the miru24 conc ...201728802410
down-regulation of malate synthase in mycobacterium tuberculosis h37ra leads to reduced stress tolerance, persistence and survival in macrophages.malate synthase is a condensing enzyme responsible for conversion of glyoxylate to malate in the presence of acetyl-coa. this reaction helps in bypassing the tca cycle reactions involving carbon loss and leads to diverting some of the carbon skeletons to gluconeogenic events while rest can continue to provide tca cycle intermediates. malate synthase (glcb) is encoded by mra_1848 of mycobacterium tuberculosis h37ra (mtb-ra). we developed a knockdown (kd) mtb-ra strain by down-regulating glcb. the ...201728802408
immunological characterization of latent tuberculosis infection in a low endemic country.the diagnosis of a latent tuberculosis infection (ltbi) is based on detection of immunity against mycobacterium tuberculosis (mtb). the tuberculin skin test (tst), the quantiferon (qft) and a prolonged lymphocyte stimulation test using either esat-6/cfp-10 (lst-ec) or ppd (lst-ppd) were evaluated in a cohort of 495 individuals, suspected to have ltbi, in a low endemic country. while the tst and lst-ppd were both positive in the majority (75%) of individuals, only one third responded in the lst-e ...201728802407
detection of mycobacterium tuberculosis from paraffin-embedded tissues by genexpert mtb/rif.genexpert mtb/rif (xpert) assay, a rapid and automated system based on real-time pcr and molecular beacon technology, proved to be a sensitive and specific tool capable of detecting mycobacterium tuberculosis and rifampin resistance in clinical specimens. in this study we provide a xpert-dedicated successful protocol for processing paraffin-embedded tissue and assess the feasibility of the xpert assay-based tuberculosis (tb) diagnosis on these specimens, thus proving the xpert assay as a valuabl ...201728802405
sustained expression of devr/dosr during long-term hypoxic culture of mycobacterium tuberculosis.devr/dosr is a key mediator of 'dormancy' adaptation in mycobacterium tuberculosis in response to gaseous stresses such as hypoxia that inhibit aerobic mode of respiration. in the present study, a temporal analysis over a 1 year period has revealed robust expression of representative devr regulon genes devr, hspx and tgs1, during long-term 'dormancy' adaptation to hypoxia. notably, a predominant proportion of long-term hypoxia-adapted bacteria were characterized by their inability to grow on sol ...201728802402
differences in igg responses against infection phase related mycobacterium tuberculosis (mtb) specific antigens in individuals exposed or not to mtb correlate with control of tb infection and progression.tuberculosis (tb) occurs in only 3-10% of mycobacterium tuberculosis (mtb) infected individuals, suggesting that natural immunity can contain mtb infection, although this remains poorly understood. next to t-cells, a potentially protective role for b-cells and antibodies has emerged recently. however, the mtb antigens involved remain ill-defined. here, we investigated in a tb-endemic setting igg levels against 15 mtb antigens, representing various phases of mtb infection and known to be potent h ...201728802401
mycobacterium tuberculosis myma is a tlr2 agonist that activate macrophages and a th1 response.cell wall of mycobacterium tuberculosis (m.tb) is a major source of immunogenic proteins that can be tested as vaccine candidates. myma (rv3083), a 55 kda m.tb flavin containing monooxygenase, is involved in modification of mycolic acids during acidic shock following m.tb internalization in macrophage. in this study, we have investigated the role of this cell wall associated protein in activation of macrophages by toll like receptor (tlrs) engagement and subsequent signaling. our results showed ...201728802400
lysx gene is differentially expressed among mycobacterium tuberculosis strains with different levels of virulence.antimicrobial peptides (amps) are mainly produced by epithelial cells and macrophages to eliminate infecting mycobacteria through direct antimicrobial activity and immunomodulation. indeed, it has been described that this line of defense is essential to control infection. however, mycobacterium tuberculosis (mtb) has developed mechanisms to avoid amps activity, for instance lysx adds lysine residues to surface phospholipids changing their net charge, leading to the repelling of the amps. in the ...201728802397
protein o-mannosylation deficiency increases lprg-associated lipoarabinomannan release by mycobacterium tuberculosis and enhances the tlr2-associated inflammatory response.protein o-mannosylation is crucial for the biology of mycobacterium tuberculosis but the key mannosylated protein(s) involved and its(their) underlying function(s) remain unknown. here, we demonstrated that the m. tuberculosis mutant (δpmt) deficient for protein o-mannosylation exhibits enhanced release of lipoarabinomannan (lam) in a complex with lprg, a lipoprotein required for lam translocation to the cell surface. we determined that lprg is o-mannosylated at a unique threonine position by ma ...201728801649
reply to valadares and woo: mechanism of rv2837c from mycobacterium tuberculosis remains controversial. 201728801353
mechanism of rv2837c from mycobacterium tuberculosis remains controversial. 201728801352
splenic tuberculosis and multifocal serpiginoid choroiditis.serpiginoid multifocal choroiditis is a distinct morphological identity with a reported causal association with mycobacterium tuberculosis. we report a case of serpiginoid multifocal choroiditis in a 17-year-old boy who was suffering from isolated splenic tuberculosis. he was treated with systemic steroids along with anti-tubercular treatment with good visual recovery. this case was unique as no other organs except spleen and choroid showed tubercular involvement. we hereby emphasize association ...201728798995
prevalence and molecular characterization of second-line drugs resistance among multidrug-resistant mycobacterium tuberculosis isolates in southwest of china.this study aimed to investigate the prevalence of multidrug-resistant tuberculosis (mdr-tb) isolates resistant to the second-line antituberculosis drugs (slds) and its association with resistant-related gene mutations in mycobacterium tuberculosis (m.tb) isolates from southwest of china. there were 81 isolates resistant to at least one of the slds among 156 mdr-tb isolates (81/156, 51.9%). the rates of general resistance to each of the drugs were as follows: ofx (66/156, 42.3%), kan (26/156, 16. ...201728798931
the utility of immunohistochemistry in mycobacterial infection: a proposal for multimodality testing.mycobacterium species are slow growing bacteria that cause significant morbidity and mortality worldwide. because of the relative rarity of mycobacterial infections, potential for detection of nonpathogenic environmental contaminants, and substantial costs associated with molecular diagnostics, effective screening methods are needed to identify samples most suitable for molecular testing. while anatomic pathology specimens can be utilized to identify characteristic histologic inflammatory patter ...201728795999
how long does antimycobacterial antibiotic-loaded bone cement have in vitro activity for musculoskeletal tuberculosis?antibiotic-loaded bone cement is accepted as an effective treatment modality for musculoskeletal tuberculosis. however, comparative information regarding combinations and concentrations of second-line antimycobacterial drugs, such as streptomycin and amoxicillin and clavulanic acid, are lacking.201728795294
the potency of chicken egg yolk immunoglobulin (igy) specific as immunotherapy to mycobacterium tuberculosis infection.the aim of this study was to characterize of chicken egg yolk immunoglobulins (igys) specific as immunotherapy to mycobacterium tuberculosis complex (mtbc) infection. lohmann laying hens were immunized intramuscularly with antigenic of mtbc. egg yolk was separated from egg white, and igy antibody was then purified by multiple polyethylene glycols 6000 extraction and ammonium sulfate purification steps. the igy anti-mtbc concentration in egg yolk increased at 2 weeks and it reached a maximum at 4 ...201728795022
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