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neurotuberculosis in cattle in southern brazil.tuberculosis in cattle is a chronic infectious-contagious disease characterized by the development of nodular lesions (granulomas) in mainly the lungs and regional lymph nodes. it is caused by mycobacterium tuberculosis complex, an acid-fast bacillus (afb). tuberculosis in the central nervous system is a rare condition in cattle. herein, we describe the clinical and pathological findings of six neurotuberculosis cases in cattle diagnosed in southern brazil. the average age of the cattle affected ...201627026233
adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, bcg-vaccinated, quantiferon(®)-tb gold (+) kenyan adults without evidence of tuberculosis.in a phase 1 trial, we evaluated the safety of aeras-402, an adenovirus 35-vectored tb vaccine candidate expressing 3 mycobacterium tuberculosis (mtb) immunodominant antigens, in subjects with and without latent mtb infection. hiv-negative, bcg-vaccinated kenyan adults without evidence of tuberculosis, 10 quantiferon(®)-tb gold in-tube test (qft-g)(-) and 10 qft-g(+), were randomized 4:1 to receive aeras-402 or placebo as two doses, on days 0 and 56, with follow up to day 182. there were no deat ...201627026148
cough aerosols of mycobacterium tuberculosis in the prediction of incident tuberculosis disease in household contacts.tuberculosis disease develops in only 5%-10% of humans infected with mycobacterium tuberculosis the mechanisms underlying this variability remain poorly understood. we recently demonstrated that colony-forming units of m. tuberculosis in cough-generated aerosols are a better predictor of infection than the standard sputum acid-fast bacilli smear. we hypothesized that cough aerosol cultures may also predict progression to tuberculosis disease in contacts.201627025837
strengthening the tuberculosis specimen referral network in uganda: the role of public-private partnerships.diagnosis of multidrug-resistant tuberculosis and prompt initiation of effective treatment rely on access to rapid and reliable drug-susceptibility testing. efficient specimen transport systems and appropriate training on specimen referral contribute to optimal and timely access to tuberculosis diagnostic services.201627025697
design and synthesis of novel quinoxaline derivatives as potential candidates for treatment of multidrug-resistant and latent tuberculosis.twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using bactiter-glo microbial cell viability assay. five compounds showed mic values <3.1 μm and ic50 values<1.5 μm in primary screening and therefore, they were moved on for further evaluation. compounds 21 and 18 stand out, showing mic values of 1.6 μm and ic50 values of 0.5 and 1.0 μm, respectively. both compounds were the most potent against three evaluated drug-resistant strains. moreover, they exhibited ...201627025343
tlr agonist augments prophylactic potential of acid inducible antigen rv3203 against mycobacterium tuberculosis h37rv in experimental animals.in general, the members of lip gene family of mycobacterium tuberculosis evoke strong immune response in the host. keeping this fact into consideration, we investigated role of rv3203, a cell wall associated protein with lipolytic activity, in imparting protection against experimental murine tuberculosis. the data of the present study suggested that archaeosome encapsulated rv3203 induce strong lymphocyte proliferation, up-regulated th-1 biased cytokines profile, increased expression of co-stimu ...201627023750
seeking potent anti-tubercular agents: design, synthesis, anti-tubercular activity and docking study of various ((triazoles/indole)-piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole derivatives.a series of thirty eight novel 3-(4-((substituted-1h-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole and 1-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1h-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against mycobacterium tuberculosis h37rv strain and two 'wild' strains spec. 210 and spec. 192. the titled compounds exhibited minimum inhi ...201627020525
synthesis and antitubercular activity of 1,2,4-trisubstitued piperazines.parallel solid phase synthesis offers a unique opportunity for the synthesis and screening of large numbers of compounds and significantly enhances the prospect of finding new leads. we report the synthesis and antitubercular activity of chiral 1,2,4-trisubstituted piperazines derived from resin bound acylated dipeptides against mycobacterium tuberculosis strain h37rv.201627020522
broad-range pcr coupled with mass-spectrometry for the detection of mycobacterium tuberculosis drug resistance.the need to limit the spread of drug-resistant mycobacterium tuberculosis requires rapid detection of resistant strains. the present study aimed to evaluate a commercial assay using broad-range pcr coupled with electrospray ionization mass spectrometry (pcr/esi-ms) for the rapid detection of isoniazid (inh) and rifampin (rif) resistance in m. tuberculosis strains isolated from romanian patients with pulmonary tuberculosis.201627019827
detection of drug resistance in mycobacterium tuberculosis. 201627019278
structure-activity relationships of a diverse class of halogenated phenazines that targets persistent, antibiotic-tolerant bacterial biofilms and mycobacterium tuberculosis.persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. here, we describe the structure-activity relationships of a series of halogenated phenazines (hp) inspired by 2-bromo-1-hydroxyphenazine 1. using multiple synthetic pathways, we probed diverse substitutions of the hp scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacte ...201627018907
disseminated bcg osteomyelitis related to stat 1 gene deficiency mimicking a metastatic neuroblastoma.mendelian susceptibility to mycobacterial disease (msmd) is a rare syndrome characterized by severe clinical infections usually caused by weakly virulent mycobacterial species such as bacillus calmette- guérin (bcg) vaccines and environmental nontuberculous mycobacteria or more virulent mycobacteria as mycobacterium tuberculosis. since 1996, nine genes including 7 autosomal (stat1, ifngr1, ifngr2, il12b, il12rb1, isg15 and irf8) and two x-linked genes (nemo and cybb) have been identified. alleli ...201627018766
a blood rna signature for tuberculosis disease risk: a prospective cohort study.identification of blood biomarkers that prospectively predict progression of mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. we aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease.201627017310
mycobacterial prevalence and antibiotic resistance frequency trends in taiwan of mycobacterial clinical isolates from 2002 to 2014.tuberculosis, caused by mycobacterium tuberculosis complex (mtbc) infections, is one of the most widespread infectious diseases worldwide. nontuberculous mycobacteria (ntm) also cause chronic pulmonary infections, however, ntm infection is generally overlooked.this study analyzed the frequencies of mtbc and ntm clinical isolates from 181,132 specimens obtained from patients in taiwan suspected of having a pulmonary mycobacterial infection from 2002 to 2014. the resistant rates to 4 first-line an ...201627015168
innate immunity holding the flanks until reinforced by adaptive immunity against mycobacterium tuberculosis infection.t cells play a cardinal role in imparting protection against mycobacterium tuberculosis (mtb). however, ample time is required before t-cells are able to evoke efficient effector responses in the lung, where the mycobacterium inflicts disease. this delay in t cells priming, which is termed as lag phase, provides sufficient time for mtb to replicate and establish itself within the host. in contrast, innate immunity efficiently curb the growth of mtb during initial phase of infection through sever ...201627014247
curcumin enhances human macrophage control of mycobacterium tuberculosis infection.with the worldwide emergence of highly drug-resistant tuberculosis (tb), novel agents that have direct antimycobacterial effects or that enhance host immunity are urgently needed. curcumin is a polyphenol responsible for the bright yellow-orange colour of turmeric, a spice derived from the root of the perennial herb curcuma longa. curcumin is a potent inducer of apoptosis-an effector mechanism used by macrophages to kill intracellular mycobacterium tuberculosis (mtb).201627012592
rs1914663 of sftpa 1 gene is associated with pediatric tuberculosis in han chinese population.surfactant protein a (sp-a), a part of the innate immune system of the lung, performs a vital role in the host defense against mycobacterium tuberculosis (mtb) infection. in order to investigate the relationship between sftpa polymorphism variations and tuberculosis (tb) in a chinese pediatric group, we conducted a case-control study using single-nucleotide polymorphism (snp) analysis. significant difference of the allelic distribution of rs1914663 in sftpa gene was observed between tb group and ...201627012150
evaluation of a whole blood chemiluminescent immunoassay of interferon-gamma inducible protein 10 (ip-10) for diagnosis of tuberculosis patients.the rapid diagnosis of bacterium-negative pulmonary tb and extra pulmonary tb is a significant problem in clinical practice.201627012046
high sequence variability of the ppe18 gene of clinical mycobacterium tuberculosis complex strains potentially impacts effectivity of vaccine candidate m72/as01e.the development of an effective vaccine is urgently needed to fight tuberculosis (tb) which is still the leading cause of death from a single infectious agent worldwide. one of the promising vaccine candidates m72/as01e consists of two proteins subunits pepa and ppe18 coded by rv0125 and rv1196. however, preliminary data indicate a high level of sequence variability among clinical mycobacterium tuberculosis complex (mtbc) strains that might have an impact on the vaccine efficacy. to further inve ...201627011018
why don't we have an effective tuberculosis vaccine yet?mycobacterium tuberculosis (m.tb) has co-evolved with humans for thousands of years, to cause tuberculosis (tb). the success of m.tb as a pathogen is in part because of the ways in which m.tb evades and exploits different cell subsets, to persist and cause disease. m.tb expresses numerous molecules to prevent its recognition and destruction by immune cells. the only licensed vaccine against tb, bacillle calmette-guerin (bcg), is effective at preventing disseminated disease in infants but confers ...201627010255
potent inhibitors of acetyltransferase eis overcome kanamycin resistance in mycobacterium tuberculosis.a major cause of tuberculosis (tb) resistance to the aminoglycoside kanamycin (kan) is the mycobacterium tuberculosis (mtb) acetyltransferase eis. upregulation of this enzyme is responsible for inactivation of kan through acetylation of its amino groups. a 123 000-compound high-throughput screen (hts) yielded several small-molecule eis inhibitors that share an isothiazole s,s-dioxide heterocyclic core. these were investigated for their structure-activity relationships. crystal structures of eis ...201627010218
rifabutin: where do we stand in 2016?rifabutin is a spiro-piperidyl-rifamycin structurally closely related to rifampicin that shares many of its properties. we attempted to address the reasons why this drug, which was recently recognized as a who essential medicine, still had a far narrower range of indications than rifampicin, 24 years after its launch. in this comprehensive review of the classic and more recent rifabutin experimental and clinical studies, the current state of knowledge about rifabutin is depicted, relying on spec ...201627009031
hiv progression perturbs the balance of the cell-mediated and anti-inflammatory adaptive and innate mycobacterial immune response.our objective is to understand how hiv infection increases the risk of progression from latent tuberculosis (tb) to active disease. we understand now that immunity is a balance of competing immune responses by multiple cell types. since t-lymphocyte production of interferon-gamma (ifn-γ) in response to mycobacterium tuberculosis (mtb) antigens fails to differentiate disease from latent infection, we applied a comprehensive profiling methodology to define immune biomarkers that reliably predict a ...201627006526
unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation.bacterial pathogens must acquire host iron for survival and colonization. because free iron is restricted in the host, numerous pathogens have evolved to overcome this limitation by using a family of monooxygenases that mediate the oxidative cleavage of heme into biliverdin, carbon monoxide, and iron. however, the etiological agent of tuberculosis, mycobacterium tuberculosis, accomplishes this task without generating carbon monoxide, which potentially induces its latent state. here we show that ...201627006503
crystal structure of mycobacterium tuberculosis h37rv aldr (rv2779c), a regulator of the ald gene: dna binding and identification of small molecule inhibitors.here we report the crystal structure of m. tuberculosis aldr (rv2779c) showing that the n-terminal dna-binding domains are swapped, forming a dimer, and four dimers are assembled into an octamer through crystal symmetry. the c-terminal domain is involved in oligomeric interactions that stabilize the oligomer, and it contains the effector-binding sites. the latter sites are 30-60% larger compared with homologs like mtbffrp (rv3291c) and can consequently accommodate larger molecules. mtbaldr binds ...201627006398
pulmonary immunity and durable protection induced by the id93/gla-se vaccine candidate against the hyper-virulent korean beijing mycobacterium tuberculosis strain k.the majority of tuberculosis (tb) vaccine candidates advanced to clinical trials have been evaluated preclinically using laboratory-adapted strains. however, it has been proposed that challenge with clinical isolates in preclinical vaccine testing could provide further and more practical validation. here, we tested the id93/gla-se tb vaccine candidate against the clinical mycobacterium tuberculosis (mtb) strain k (mtb k) belonging to the beijing family, the most prevalent mtb strain in south kor ...201627005808
mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance.combating the spread of drug resistant tuberculosis is a global health priority. whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance.201627005572
[polymorphisms of toxin-antitoxin-chaperone system of mycobacterium tuberculosis complex in china].to investigate the single nucleotide polymorphism (snp) of toxin-antitoxin-chaperone (tac) system of mycobacterium (m.) tuberculosis with different genotypes and its biological significance.201627005544
identification of ofloxacin-resistant mycobacterium tuberculosis by pcr-rflp and sequencing.this study was planned to verify the resistance frequency of ofloxacin (ofx) against mycobacterium tuberculosis by polymerase chain reaction restriction fragment length polymorphism (pcr-rflp) technique and sequencing. total 366 clinical samples of suspected tb patients were collected from various localities of central punjab. all of them were found positive by zn (zeihl-nelsen) staining method. among them, 108 (29.5%) were found negative and 258 (70.5%) positive on pcr based study. the cases no ...201627005504
clinical use of whole genome sequencing for mycobacterium tuberculosis.drug-resistant tuberculosis (tb) remains a major challenge to global health and to healthcare in the uk. in 2014, a total of 6,520 cases of tb were recorded in england, of which 1.4 % were multidrug-resistant tb (mdr-tb). extensively drug-resistant tb (xdr-tb) occurs at a much lower rate, but the impact on the patient and hospital is severe. current diagnostic methods such as drug susceptibility testing and targeted molecular tests are slow to return or examine only a limited number of target re ...201627004841
differences in cultural yield of mycobacterium tuberculosis on media prepared using commercial and household eggs.mycobacterial culture is considered as the gold standard for tb diagnosis. it is performed on egg-based media using commercially available eggs to grow mycobacteria from clinical samples. these eggs are known to contain high concentration of antibiotics, including fluoroquinolones, given to chicken to prevent early mortality. this study was performed to compare mycobacterial growth on media prepared from commercial and antibiotic free household eggs.201627004317
comprehensive definition of the sigh regulon of mycobacterium tuberculosis reveals transcriptional control of diverse stress responses.expression of sigh, one of 12 mycobacterium tuberculosis alternative sigma factors, is induced by heat, oxidative and nitric oxide stresses. sigh activation has been shown to increase expression of several genes, including genes involved in maintaining redox equilibrium and in protein degradation. however, few of these are known to be directly regulated by sigh. the goal of this project is to comprehensively define the mycobacterium tuberculosis genes and operons that are directly controlled by ...201627003599
interleukin 8 gene polymorphisms are not associated with tuberculosis susceptibility in the chinese population.interleukin 8 (il8) is an important chemokine that elicits host immune response against tuberculosis (tb). however, whether there is an association between il8 gene polymorphism and tb susceptibility in the chinese population is unknown. il8 gene was amplified and sequenced to search for nucleotide polymorphisms among the chinese population. four single nucleotide polymorphisms (snps) were identified, selected, and analyzed in a cohort of 438 patients with tb and 536 healthy controls. allelic, g ...201627003175
prevalence and risk factors of primary drug-resistant tuberculosis in china.to investigate the prevalence of primary drug-resistant tuberculosis (tb) and associated risk factors in china. we also explored factors contributing to the transmission of multidrug-resistant tuberculosis (mdr-tb).201627003166
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
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