Publications

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asymmetric total synthesis of (-)-erogorgiaene and its c-11 epimer and investigation of their antimycobacterial activity.a short, nine-step, highly enantioselective synthesis of (-)-erogorgiaene and its c-11 epimer is reported. the key stereochemistry controlling steps involve catalytic asymmetric crotylation, anionic oxy-cope rearrangement and cationic cyclisation. (-)-erogorgiaene exhibited promising antitubercular activity against multidrug-resistant strains of mycobacterium tuberculosis.201627529822
tuberculous cellulitis: diseases behind cellulitislike erythema.an 89-year-old man presented with an inflammatory erythematous plaque on the left thigh that closely mimicked cellulitis. empiric therapies with ordinary antibiotics were not effective. a skin biopsy showed epithelioid cell granulomas throughout the dermis and subcutis. ziehl-neelsen stain revealed numerous acid-fast bacilli. additionally, mycobacterium tuberculosis was isolated from a skin biopsy specimen as well as gastric fluid and sputum cultures. he was diagnosed with tuberculous cellulitis ...201627529716
immunotherapy for tuberculosis: future prospects.tuberculosis (tb) is still a major global health problem. a third of the world's population is infected with mycobacterium tuberculosis. only ~10% of infected individuals develop tb but there are 9 million tb cases with 1.5 million deaths annually. the standard prophylactic treatment regimens for latent tb infection take 3-9 months, and new cases of tb require at least 6 months of treatment with multiple drugs. the management of latent tb infection and tb has become more challenging because of t ...201627529060
in vitro mycobacterial growth inhibition assays: a tool for the assessment of protective immunity and evaluation of tuberculosis vaccine efficacy.tuberculosis (tb) continues to pose a serious global health threat, and the current vaccine, bcg, has variable efficacy. however, the development of a more effective vaccine is severely hampered by the lack of an immune correlate of protection. candidate vaccines are currently evaluated using preclinical animal models, but experiments are long and costly and it is unclear whether the outcomes are predictive of efficacy in humans. unlike measurements of single immunological parameters, mycobacter ...201627527814
stringent response factors ppx1 and ppk2 play an important role in mycobacterium tuberculosis metabolism, biofilm formation, and sensitivity to isoniazid in vivo.mycobacterium tuberculosis remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. this prolonged therapy is likely due to the presence of m. tuberculosis persisters, which exhibit antibiotic tolerance. inorganic polyphosphate [poly(p)] is a key regulatory molecule in the m. tuberculosis stringent response mediating antibiotic tolerance. the polyphosphate kinase ppk1 is respons ...201627527086
characterization of dpre1-mediated benzothiazinone resistance in mycobacterium tuberculosis.benzothiazinones (btzs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant mycobacterium tuberculosis strains. the potency of btzs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (dpre1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. to probe the role of c387, we used promiscuous site-directed mutagenesis to introduce other cod ...201627527085
evaluation of a whole-blood chemiluminescent immunoassay of ifn-γ, ip-10, and mcp-1 for diagnosis of active pulmonary tuberculosis and tuberculous pleurisy patients.the study explored the use of ip-10, mcp-1, and ifn-γ as biomarkers to improve the diagnoses of active pulmonary tuberculosis and tuberculous pleurisy. we enrolled 267 individuals, including 134 tb patients, 93 patients with non-tuberculous pulmonary diseases, and 40 healthy controls. whole bloods were stimulated in vitro with rcfp-10/esat-6 protein antigen of mycobacterium tuberculosis. the levels of ifn-γ, ip-10, and mcp-1 in cultured supernatants of whole bloods were detected by a chemilumine ...201627523388
rifampicin resistance mutations in the 81 bp rrdr of rpob gene in mycobacterium tuberculosis clinical isolates using xpert mtb/rif in khyber pakhtunkhwa, pakistan: a retrospective study.multi-drug resistant tuberculosis (mdr-tb) is a major public health problem especially in developing countries. world health organization (who) recommends use of xpert mtb/rif assay to simultaneously detecting mycobacterium tuberculosis (mtb) and rifampicin (rif) resistance. the primary objective of this study was to determine the frequency of mdr-tb in patients suspected to have drug resistance in khyber pakhtunkhwa. the frequency of probes for various rpob gene mutations using xpert mtb/rif as ...201627519406
whole-genome sequencing analysis of serially isolated multi-drug and extensively drug resistant mycobacterium tuberculosis from thai patients.multi-drug and extensively drug-resistant tuberculosis (mdr and xdr-tb) are problems that threaten public health worldwide. only some genetic markers associated with drug-resistant tb are known. whole-genome sequencing (wgs) is a promising tool for distinguishing between re-infection and persistent infection in isolates taken at different times from a single patient, but has not yet been applied in mdr and xdr-tb. we aim to detect genetic markers associated with drug resistance and distinguish b ...201627518818
analysis of mycobacterium tuberculosis genotypic lineage distribution in chile and neighboring countries.tuberculosis (tb), caused by the pathogen mycobacterium tuberculosis (mtb), remains a disease of high importance to global public health. studies into the population structure of mtb have become vital to monitoring possible outbreaks and also to develop strategies regarding disease control. although chile has a low incidence of mtb, the current rates of migration have the potential to change this scenario. we collected and analyzed a total of 458 m. tuberculosis isolates (1 isolate per patient) ...201627518286
molecular detection of mycobacterium tuberculosis in cattle and buffaloes: a cause for public health concern.tuberculosis is a re-emerging disease causing a growing public health burden. the current study was conducted to investigate the occurrence of mycobacterium tuberculosis among cattle and buffaloes with tuberculous lesions. typical tuberculous lesions were collected from 34 cattle and 34 buffaloes (bubalus bubalis) through postmortem examination of slaughtered animals in abattoirs. dnas were extracted from samples, and m. tuberculosis was identified by pcr. positive samples were examined for resi ...201627517579
first-line anti-tubercular drug resistance of mycobacterium tuberculosis in iran: a systematic review.the spread of drug-resistant tuberculosis (tb) is one of the major public health problems through the world. surveillance of anti-tb drug resistance is essential for monitoring of tb control strategies. the occurrence of drug resistance, particularly multi-drug resistance mycobacterium tuberculosis (mdr), defined as resistance to at least rifampicin (rif) and isoniazid (inh), has become a significant public health dilemma. the status of drug-resistance tb in iran, one of the eastern mediterranea ...201627516756
official american thoracic society/centers for disease control and prevention/infectious diseases society of america clinical practice guidelines: treatment of drug-susceptible tuberculosis.the american thoracic society, centers for disease control and prevention, and infectious diseases society of america jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the european respiratory society and the us national tuberculosis controllers association. representatives from the american academy of pediatrics, the canadian thoracic society, the international union against tuberculosis and lung disease, and the wo ...201627516382
comparison of maldi-tof ms, nucleic acid hybridization and the mpt64 immunochromatographic test for the identification of m. tuberculosis and non-tuberculosis mycobacterium species.mycobacteria are an important cause of morbidity in humans. rapid and accurate mycobacterial identification is important for improving patient outcomes. however, identification of mycobacterium species is not easy, due to the slow and fastidious growth of mycobacteria. recently, biochemical, sequencing, and probing methods have come to be used for identification. this study compared the performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (maldi-tof ms) for ...201627551724
hypoxia and classical activation limits mycobacterium tuberculosis survival by akt-dependent glycolytic shift in macrophages.cellular reactive oxygen species (ros) is a major antibacterial defense mechanism used by macrophages upon activation. exposure of mycobacterium tuberculosis (mtb)-infected macrophages to hypoxia is known to compromise the survival of the pathogen. here we report that the hypoxia-induced control of intracellular mtb load in raw 264.7 macrophages was mediated by regulating the cellular ros levels. we show that similar to classical activation, hypoxia incubation of macrophages resulted in decrease ...201627551515
early bactericidal activity of azd5847 in patients with pulmonary tuberculosis.azd5847 is an oxazolidinone antibiotic with in vitro activity against mycobacterium tuberculosis the objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of azd5847 in patients with pulmonary tuberculosis. groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive azd5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily st ...201627550361
hiv-1 tat protein vaccination in mice infected with mycobacterium tuberculosis is safe, immunogenic and reduces bacterial lung pathology.the therapeutic hiv-1 tat protein vaccine is in advanced clinical development. tuberculosis, the main aids co-infection, is highly endemic in areas where aids prevention through vaccination is needed. however, safety and immunogenicity of tat vaccination in the course of mycobacterium tuberculosis (mtb) infection is still unknown and it prevents the possibility to administer the vaccine to mtb-infected individuals. we addressed the interplay and effects of tat vaccination on mtb infection in imm ...201627549342
direct matrix-assisted laser desorption ionisation time-of-flight mass spectrometry identification of mycobacteria from colonies.matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (maldi-tof-ms) identification of mycobacteria requires a standard acetonitrile/formic acid pre-maldi-tof-ms. we prospectively compared this standard protocol with direct deposit with matrix for the identification of mycobacteria cultured on solid media. we first verified that mycobacterium tuberculosis was killed after it was mixed with matrix. then, 111 mycobacterium isolates previously identified by partial rpob gene ...201627549109
plastic-chip-based magnetophoretic immunoassay for point-of-care diagnosis of tuberculosis.tuberculosis (tb) remains a relevant infectious disease in the 21st century, and its extermination is still far from being attained. due to the extreme infectivity of incipient tb patients, a rapid sensing system for proficient point-of-care (poc) diagnostics is required. in our study, a plastic-chip-based magnetophoretic immunoassay (pcmpi) is introduced using magnetic and gold nanoparticles (nps) modified with mycobacterium tuberculosis (mtb) antibodies. this pcmpi offers an ultrasensitive lim ...201627548010
structure of the essential mtb fadd32 enzyme: a promising drug target for treating tuberculosis.mycolic acids are indispensible lipids of mycobacterium tuberculosis (mtb), the causative agent of tuberculosis (tb), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. fadd32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (fas) and polyketide synthase (pks) biosynthetic pathways. fadd32, a fatty acyl-amp ligase (faal), represents one of the best genetically and chemically validated new tb drug targ ...201627547819
new strain multidrug resistant tuberculosis g24767 in puerto rico: old disease a continuous threat.multidrug resistant tuberculosis (mdr-tb) is defined as a mycobacterium tuberculosis strain resistant to two or more first-line anti-tuberculous drugs. tuberculosis (tb) is a global threat to society despite improvement in therapy as it continues to be an economic burden especially in underdeveloped countries. the downfall of global economics and growing travel destinations in developing countries has escalade the exposure of organism not previously encountered in industrialized nations. most ca ...201627547724
do not feed the wildlife: associations between garbage use, aggression, and disease in banded mongooses (mungos mungo).urbanization and other human modifications of the landscape may indirectly affect disease dynamics by altering host behavior in ways that influence pathogen transmission. few opportunities arise to investigate behaviorally mediated effects of human habitat modification in natural host-pathogen systems, but we provide a potential example of this phenomenon in banded mongooses (mungos mungo), a social mammal. our banded mongoose study population in botswana is endemically infected with a novel myc ...201627547366
the bcgδbcg1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo.mycobacterium tuberculosis (mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (tb). until today, the only licensed vaccine against mtb is the live attenuated m. bovis bacillus calmette-guérin (bcg), which has variable levels of protection against the pulmonary form of infection. the quest for a new vaccine is a priority given the rise of multidrug-resistant mtb around the world, as well as the tremendous burden imposed by latent tb. the obje ...201627546876
new tests for detection of mycobacterium tuberculosis infection: sufficient to meet the who 2035 targets? 201627545599
rifapentine for the treatment of latent tuberculosis.the goal of this article is to review the use of rifapentine in the treatment of latent tuberculosis infection (ltbi). controlling ltbi is an important part of the global strategy to end the spread of tuberculosis. rifapentine's potent sterilizing effect against mycobacterium tuberculosis combined with its long half-life make it an attractive ltbi treatment option.201627545595
proteomic and morphological changes produced by subinhibitory concentration of isoniazid in mycobacterium tuberculosis.to study the proteomic and morphological changes in mycobacterium tuberculosis h37rv exposed to subinhibitory concentration of isoniazid (inh).201627545345
strain differentiation of mycobacterium tuberculosis for epidemiology in northwest of iran.tuberculosis is a major health problem throughout the world and there are still a great number of people with the disease. planning for controlling tuberculosis is required to identify the sources of infection and screening for the disease. the aim of this study is the differentiation of mycobacterium tuberculosis strains for better understands the spread of the disease in north west iran. in this study, 194 positive cultures of m. tuberculosis in north west iran were evaluated by the miru-vntr ...201627545209
binding sites for acylated trehalose analogs of glycolipid ligands on an extended carbohydrate recognition domain of the macrophage receptor mincle.the macrophage receptor mincle binds to trehalose dimycolate on the surface of mycobacterium tuberculosis signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. in previous work the mechanism for binding of the sugar headgroup of trehalose dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are a ...201627542410
genotypic detection of rpob and katg gene mutations associated with rifampicin and isoniazid resistance in mycobacterium tuberculosis isolates: a local scenario (kelantan).drug resistant tuberculosis (dr-tb) remains a public health issue that is of major concern on a global scale. the characterisation of clinical isolates may provide key information regarding the underlying mechanisms of drug resistance, and helps to augment therapeutic options. this study aims to evaluate the frequency of gene mutations associated with rifampicin (rif) and isoniazid (inh) resistance among nine clinical isolates.201627540322
corrigendum to "katg ser315 and rpob 81-bp hotspot region substitutions: reliability for detection of drug-resistant strains of mycobacterium tuberculosis" [j. global antimicrob. resist. 5 (2016) 92-93]. 201627553705
safety and immunogenicity of the m72/as01e candidate tuberculosis vaccine in adults with tuberculosis: a phase ii randomised study.previous studies have shown that the m72/as01e candidate tuberculosis vaccine is immunogenic with a clinically acceptable safety profile in healthy and mycobacterium tuberculosis-infected adults. this phase ii, observer-blind, randomised study compared the safety, reactogenicity, and immunogenicity of m72/as01e in 3 cohorts: tuberculosis-naïve adults (n = 80), adults previously treated for tuberculosis (n = 49), and adults who have completed the intensive phase of tuberculosis treatment (n = 13) ...201627553419
loop-mediated isothermal amplification (lamp) assay for speedy diagnosis of tubercular lymphadenitis: the multi-targeted 60-minute approach.tuberculous lymphadenitis (tbla), the most common presentation of tuberculosis, poses a significant diagnostic challenge in the developing countries. timely, accurate and cost-effective diagnosis can decrease the high morbidity associated with tbla especially in resource-poor high-endemic regions. the loop-mediated isothermal amplification assay (lamp), using two targets, was evaluated for the diagnosis of tbla.201627553418
dissecting host factors that regulate the early stages of tuberculosis infection.incomplete understanding of mechanisms involved in the host-pathogen interactions constrains our efforts to eliminate tuberculosis. in many individuals, resulting from immune response to mycobacterial infection organised structures called granulomas are formed. to identify host responses that may control at least the early stages of infection, we employed an in vitro granuloma model. here, human pbmcs were infected with live mycobacterium tuberculosis in culture, and the appearance of granuloma- ...201627553417
micrococcin p1 - a bactericidal thiopeptide active against mycobacterium tuberculosis.the lack of proper treatment for serious infectious diseases due to the emergence of multidrug resistance reinforces the need for the discovery of novel antibiotics. this is particularly true for tuberculosis (tb) for which 3.7% of new cases and 20% of previously treated cases are estimated to be caused by multi-drug resistant strains. in addition, in the case of tb, which claimed 1.5 million lives in 2014, the treatment of the least complicated, drug sensitive cases is lengthy and disagreeable. ...201627553416
sputum is a surrogate for bronchoalveolar lavage for monitoring mycobacterium tuberculosis transcriptional profiles in tb patients.pathogen-targeted transcriptional profiling in human sputum may elucidate the physiologic state of mycobacterium tuberculosis (m. tuberculosis) during infection and treatment. however, whether m. tuberculosis transcription in sputum recapitulates transcription in the lung is uncertain. we therefore compared m. tuberculosis transcription in human sputum and bronchoalveolar lavage (bal) samples from 11 hiv-negative south african patients with pulmonary tuberculosis. we additionally compared these ...201627553415
immunoglobulin g response to mammalian cell entry 1a (mce1a) protein as biomarker of active tuberculosis.cell wall components are major determinants of virulence of mycobacterium tuberculosis and they contribute to the induction of both humoral and cell-mediated immune response. the mammalian cell entry protein 1a (mce1a), in the cell wall of m. tuberculosis, mediates entry of the pathogen into mammalian cells. here, we examined serum immunoglobulin levels (iga, igm and total igg) against mce1a as a potential biomarker for diagnosis and monitoring tuberculosis (tb) treatment response. serum samples ...201627553414
a snapshot of the predominant single nucleotide polymorphism cluster groups of mycobacterium tuberculosis clinical isolates in delhi, india.several attempts have been made to associate phylogenetic differences among mycobacterium tuberculosis strains to variations in the clinical outcome of the disease and to drug resistance. we genotyped 139 clinical isolates of m. tuberculosis obtained from patients of pulmonary tuberculosis in north delhi region. the isolates were analyzed using nine single nucleotide polymorphism (snp) markers, spoligotyping and miru-vntrs; and the results were correlated with their drug susceptibility profile. ...201627553413
mmpl transporter-mediated export of cell-wall associated lipids and siderophores in mycobacteria.mycobacteria produce a large variety of surface-exposed lipids with unusual structures. some of these compounds are ubiquitously present in mycobacteria and play an important role in the structural organization of the cell envelope, while others are species-specific. the biosynthesis of most of these lipids requires modular polyketide synthases (pks) or non-ribosomal peptide synthetases (nrps) that are intracellular, suggesting that the assembly of these compounds takes place in the cytosolic co ...201627553408
comparative study of enzymatic activities of new katg mutants from low- and high-level isoniazid-resistant clinical isolates of mycobacterium tuberculosis.resistance to isoniazid (inh-r) in mycobacterium tuberculosis is mainly due to mutations at position 315 (s315t) of the catalase-peroxidase katg. we identified 16 mutations (including 13 biochemically uncharacterized mutations) in katg from inh-r clinical isolates of m. tuberculosis showing mutations other than s315t. the katg enzymatic activities (catalase, peroxidase, free radical production and isonicotinoyl-nad formation) of wild-type katg and the 16 mutants were determined and correlated to ...201627553406
evaluation of multiplex pcr using mpb64 and is6110 primers for rapid diagnosis of tuberculous meningitis.tuberculous meningitis (tbm) is one of those most serious manifestations of extra-pulmonary tuberculosis and prompt diagnosis and treatment is required for better clinical outcome. it is difficult to diagnose due to lack of rapid, sensitive, and specific tests. newer methods, which are easy and reliable, are required to diagnose tbm at an early stage. thus our aim was to evaluate the multiplex polymerase chain reaction (pcr) technique, using primers directed against the insertion sequence is6110 ...201627553404
tuberculosis and its management: an overview.tuberculosis (tb) is a primordial infectious disease that mainly affects the lungs. mycobacterium tuberculosis (m. tuberculosis) is the etiological agent of tb and currently more than one-third of the world population is suffering from tb. for the treatment of tb, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for long time period to kill the bacteria. therefore antibiotic resistance is the emerging problem in multiple drug-resistant ...201627553018
the role of prostate apoptosis response-4 (par-4) in mycobacterium tuberculosis infected macrophages.prostate apoptosis response-4 (par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (grp78) to induce apoptosis. previously, we reported that er stress-induced apoptosis is a critical host defense mechanism against mycobacterium tuberculosis (mtb). we sought to understand the role of par-4 during er stress-induced apoptosis in response to mycobacterial infection. par-4 and grp78 protein levels increased in response mtb (strain: h37ra) infection. furthermore ...201627552917
tuberculosis screening: an update for nps.one-third of the world's population is infected with mycobacterium tuberculosis. if nps are to effectively participate in eliminating and preventing tuberculosis (tb), they must be cognizant of the current cdc-approved tb screening methods and guidelines.201627552684
mycobacterium tuberculosis (mtb) gyrb inhibitors: an attractive approach for developing novel drugs against tb.new classes of drugs are needed to treat tuberculosis (tb) in order to combat the emergence of resistance (mdr and xdr) to existing agents and shorten the duration of therapy. mycobacterial dna gyrase b subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. in the present review, we discussed the synthesis, structural optimization and docking study of effective potent dna gyrase inhibitor against m. tuberculosis, with ...201627569197
mycobacterium tuberculosis lppm displays an original structure and domain composition linked to a dual localization.mycobacterium tuberculosis (mtb) encodes several bacterial effectors impacting the colonization of phagocytes. lppm (rv2171) is both implicated in phagocytosis and able to efficiently block phagosomal acidification in the macrophage, two key processes contributing to mtb persistence. we show that lppm is anchored to the mycobacterial cell wall by a c-terminal membrane domain. however, the protein also exists as a truncated protein secreted into the culture medium. the lppm solution structure we ...201627568926
identification of mycobacterium spp. and nocardia spp. from solid and liquid cultures by matrix-assisted laser desorption ionization-time of flight mass spectrometry (maldi-tof ms).identification of microorganisms by maldi-tof ms has been widely accepted in clinical microbiology. however, for mycobacterium spp. and nocardia spp. such identification has not yet reached the optimal level of routine testing. here we describe the development of an identification tool for 49 and 15 species of mycobacterium spp. and nocardia spp., respectively. during database construction, a number of ambiguous reference identifications were revealed and corrected via molecular analyses. eventu ...201627567285
drug-resistant tuberculosis viewed from bacterial and host genomes.the outcome of infection with mycobacterium tuberculosis (mtb) is largely influenced by the host-pathogen interaction in which both the human host and the mtb genetic backgrounds play an important role. whether this interaction also influences the selection and expansion of drug-resistant mtb strains is the primary focus of this review. we first outline the main and recent findings regarding mtb determinants implicated in the development of drug resistance. second, we examine data regarding huma ...201627566907
mycobacterium tuberculosis multistage antigens confer comprehensive protection against pre- and post-exposure infections by driving th1-type t cell immunity.there is an urgent need for a vaccine against tuberculosis (tb) that is more effective than the current sole licensed option. however, target antigens of mycobacterium tuberculosis with the vaccine potential remain elusive. five immunodominant antigens with characteristic expressions at the stages of primary infection (ag85a), the regulation of nutrition and metabolism when transferring from rapid growth to latency (phoy2 and rv3407), latency (rv2626c), and reactivation (rpfb) were selected to c ...201627566581
spatio-temporal distribution of mycobacterium tuberculosis complex strains in ghana.there is a perception that genomic differences in the species/lineages of the nine species making the mycobacterium tuberculosis complex (mtbc) may affect the efficacy of distinct control tools in certain geographical areas. we therefore analyzed the prevalence and spatial distribution of mtbc species and lineages among isolates from pulmonary tb cases over an 8-year period, 2007-2014.201627564240
synthesis and antitubercular activity of new benzo[b]thiophenes.in vitro and ex vivo efficacies of four series of benzo[b]thiophene-2-carboxylic acid derivatives were studied against mycobacterium tuberculosis h37ra (mtb). benzo[b]thiophenes were also tested in vitro against multidrug resistant mycobacterium tuberculosis h37ra (mdr-mtb), and 7b was found to be highly active against a- and d-mdr-mtb/mtb (mic ranges 2.73-22.86 μg/ml). the activity of all benzo[b]thiophenes against m. bovis bcg (bcg) was also assessed grown under aerobic and under conditions of ...201627563398
a subunit vaccine based on rh-ns induces protection against mycobacterium tuberculosis infection by inducing the th1 immune response and activating macrophages.mycobacterium tuberculosis (mtb) is a gram-positive pathogen which causes tuberculosis in both animals and humans. all tested rh-ns formulations induced a specific th1 response, as indicated by increased production of interferon γ (ifn-γ) and interleukin 2 (il-2) by lymphocytes in the spleen of mice which were immunized with rh-ns alone or with rh-ns and the adjuvant cyclic gmp-amp (cgamp). serum from mice immunized with rh-ns with or without adjuvant also had higher levels of il-12p40 and tnf-α ...201627563010
suppression of autophagy and antigen presentation by mycobacterium tuberculosis pe_pgrs47.suppression of major histocompatibility complex (mhc) class ii antigen presentation is believed to be among the major mechanisms used by mycobacterium tuberculosis to escape protective host immune responses. through a genome-wide screen for the genetic loci of m. tuberculosis that inhibit mhc class ii-restricted antigen presentation by mycobacteria-infected dendritic cells, we identified the pe_pgrs47 protein as one of the responsible factors. targeted disruption of the pe_pgrs47 (rv2741) gene l ...201627562263
antimycobacterial metabolites from marine invertebrates.marine organisms play an important role in natural product-based drug research due to accumulation of structurally unique and bioactive metabolites. the exploration of marine-derived compounds may significantly extend the scientific knowledge of potential scaffolds for antibiotic drug discovery. development of novel antitubercular agents is especially significant as the emergence of drug-resistant mycobacterium tuberculosis strains remains threateningly high. marine invertebrates (i.e., sponges, ...201627561360
deoxyfluoro-d-trehalose (fdtre) analogues as potential pet probes for imaging mycobacterial infection.mycobacterium tuberculosis, the etiological agent of human tuberculosis, requires the non-mammalian disaccharide trehalose for growth and virulence. recently, detectable trehalose analogues have gained attention as probes for studying trehalose metabolism and as potential diagnostic imaging agents for mycobacterial infections. of particular interest are deoxy-[(18)f]fluoro-d-trehalose ((18)f-fdtre) analogues, which have been suggested as possible positron emission tomography (pet) probes for in ...201627560008
investments in tuberculosis research - what are the gaps?through decades of research, numerous studies have generated robust evidence about effective interventions for tuberculosis control. yet, the global annual decline in incidence of approximately 1 % is evidence that current approaches and investment strategies are not sufficient. in this article, we assess recent tuberculosis research funding and discuss two critical gaps in funding and in scientific evidence from topics that have been left off the research priority agenda.we first examine resear ...201627558175
mycobacterium tuberculosis phosphate uptake system component psta2 is not required for gene regulation or virulence.the mycobacterium tuberculosis genome encodes two complete high-affinity pst phosphate-specific transporters. we previously demonstrated that a membrane-spanning component of one pst system, psta1, was essential both for m. tuberculosis virulence and for regulation of gene expression in response to external phosphate availability. to determine if the alternative pst system is similarly required for virulence or gene regulation, we constructed a deletion of psta2. transcriptome analysis revealed ...201627557082
chemical insight into the mechanism and specificity of glft2, a bifunctional galactofuranosyltransferase from mycobacteria.mycobacteria, including the human pathogen mycobacterium tuberculosis, produce a complex cell wall structure that is essential to survival. a key component of this structure is a glycoconjugate, the mycolyl-arabinogalactan-peptidoglycan complex, which has at its core a galactan domain composed of galactofuranose (galf) residues linked to peptidoglycan. because galactan biosynthesis is essential for mycobacterial viability, compounds that interfere with this process are potential therapeutic agen ...201627557056
whole genome sequencing of mycobacterium tuberculosis sb24 isolated from sabah, malaysia.mycobacterium tuberculosis (m. tuberculosis) is the causative agent of tuberculosis (tb) that causes millions of death every year. we have sequenced the genome of m. tuberculosis isolated from cerebrospinal fluid (csf) of a patient diagnosed with tuberculous meningitis (tbm). the isolated strain was referred as m. tuberculosis sb24. genomic dna of the m. tuberculosis sb24 was extracted and subjected to whole genome sequencing using pacbio platform. the draft genome size of m. tuberculosis sb24 w ...201627556011
crystal structure of vapc21 from mycobacterium tuberculosis at 1.31 å resolution.persisters are individual bacterial cells that exhibit a phenotype characterized by slow growth, low metabolic rate and multidrug tolerance. the processes that drive cells into a persistence state constitute an active but incipient research field, and structural data regarding its components are scarce. the molecular targets of many therapeutic drugs are involved in cell wall synthesis and cell division, and these cellular processes are down-regulated in persister cells, consequently these cells ...201627576202
plasma adenosine deaminase enzyme reduces with treatment of pulmonary tuberculosis in nigerian patients: indication for diagnosis and treatment monitoring.tuberculosis(tb)-specific host biomarkers for diagnosis and monitoring of treatment response have been identified as priorities for tb research. macrophage and t cell lymphocytes play vital roles in mycobacterium tuberculosis immune response and their associated biomarkers could form good candidates for diagnosis and treatment monitoring. the enzyme adenosine deaminase (ada) is produced mainly by monocytes and macrophages and increase in biological fluids in the course of infection with microorg ...201627574764
network analysis identifies rv0324 and rv0880 as regulators of bedaquiline tolerance in mycobacterium tuberculosis.the resilience of mycobacterium tuberculosis (mtb) emerges from its ability to effectively counteract immunological, environmental and antitubercular challenges. here, we demonstrate that mtb can tolerate drug treatment by adopting a tolerant state that can be deciphered through systems analysis of its transcriptional responses. specifically, we demonstrate how treatment with the antitubercular drug bedaquiline activates a regulatory network that coordinates multiple resistance mechanisms to pus ...201627573104
structural insight into dephosphorylation by trehalose 6-phosphate phosphatase (otsb2) from mycobacterium tuberculosis.trehalose serves as a key structural component in the cell wall of mycobacterium tuberculosis. m. tuberculosis trehalose-6-phosphate phosphatase (mtbtpp), an essential enzyme in the trehalose biosynthesis otsab pathway, catalyzes the dephosphorylation of trehalose-6-phosphate (trehalose-6-p) to generate trehalose, and plays a critical role in m. tuberculosis survival-associated cell wall formation and permeability. therefore, mtbtpp (otsb2) is considered a promising potential target for discover ...201627572957
role of cathepsins in mycobacterium tuberculosis survival in human macrophages.cathepsins are proteolytic enzymes that function in the endocytic pathway, especially in lysosomes, where they contribute directly to pathogen killing or indirectly, by their involvement in the antigen presentation pathways. mycobacterium tuberculosis (mtb) is a facultative intracellular pathogen that survives inside the macrophage phagosomes by inhibiting their maturation to phagolysosomes and thus avoiding a low ph and protease-rich environment. we previously showed that mycobacterial inhibiti ...201627572605
bioluminescent reporters for rapid mechanism of action assessment in tuberculosis drug discovery.the tuberculosis (tb) drug discovery pipeline is fueled by compounds identified in whole-cell screens against the causative agent, mycobacterium tuberculosis phenotypic screening enables the selection of molecules that inhibit essential cellular functions in live, intact bacilli grown under a chosen in vitro condition. however, deducing the mechanism of action (moa), which is important to avoid promiscuous targets, often requires significant biological resources in a lengthy process that risks d ...201627572410
genomic analysis of the evolution of fluoroquinolone resistance in mycobacterium tuberculosis prior to tuberculosis diagnosis.fluoroquinolones (fqs) are effective second-line drugs for treating antibiotic-resistant tuberculosis (tb) and are being considered for use as first-line agents. because fqs are used to treat a range of infections, in a setting of undiagnosed tb, there is potential to select for drug-resistant mycobacterium tuberculosis mutants during fq-based treatment of other infections, including pneumonia. here we present a detailed characterization of ofloxacin-resistant m. tuberculosis samples isolated di ...201627572408
thpp target assignment reveals echa6 as an essential fatty acid shuttle in mycobacteria.phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. however, reliable target identification remains challenging. here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (thpp) selectively pulls down echa6 in a stereospecific manner, instead of the previously assigned target mycobacterium tuberculosis mmpl3. while homologous to mammalian enoyl-coenzyme a (coa) hydratases, echa6 is non-catalytic yet essential and bin ...201627571973
blockade of the kv1.3 k+ channel enhances bcg vaccine efficacy by expanding central memory t lymphocytes.tuberculosis is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary tuberculosis. emerging evidence indicates that t-helper 1 and t-helper 17 cells play important roles in host protection against tuberculosis. however, tuberculosis vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory t (tcm) and effector memory t (tem) cells. specifically, a high tcm/tem cell ratio is essential for optimal vaccine effic ...201627571906
acute respiratory distress syndrome complicating community-acquired pneumonia secondary to mycobacterium tuberculosis in a tertiary care center in saudi arabia.to discuss our center's experience with acute respiratory distress syndrome (ards) secondary to pulmonary tuberculosis (tb) in a major tertiary referral hospital in the kingdom of saudi arabia.201627570853
two-year follow-up study of mycobacterium tuberculosis antigen-driven ifn-γ responses and macrophage scd14 levels after tuberculosis contact.clinical data regarding the prediction of active tuberculosis (tb) development in close tb contacts are scarce. to address this problem, we performed a 2-year follow-up study of mycobacterium tuberculosis (m.tb) antigen-driven ifn-gamma responses and serum levels of soluble macrophage cd14 receptor in individuals with recent or prolonged m.tb exposure. between june 2011 and june 2013, we studied 60 healthy polish adults with recent household or long-term work tb contact and individuals without k ...201627570313
mycobacterium aurum is unable to survive mycobacterium tuberculosis latency associated stress conditions: implications as non-suitable model organism.mycobacterium tuberculosis manages to remain latent in the human body regardless of extensive chemotherapy. complete eradication of tuberculosis (tb) requires treatment strategies targeted against latent form of infection, in addition to the current regimen of antimycobacterials. many in vitro and in vivo models have been proposed to imitate latent tb infection, yet none of them is able to completely mimic latent infection state of m. tuberculosis. highly infectious nature of the pathogen requir ...201627570312
gene therapy based in antimicrobial peptides and proinflammatory cytokine prevents reactivation of experimental latent tuberculosis.mycobacterium tuberculosis (mtb) latent infection can lead to reactivation. the design of new strategies to prevent it is an important subject. b6d2f1 mice were infected intratracheally with a low dose of mtb h37rv to induce chronic infection. after 7 months, mice were treated with one dose of recombinant adenoviruses encoding tnfα, β defensin-3 and ll37. immunosupression was induced 1 month later with corticosterone. in comparison with the control group, mice treated with adenoviruses showed si ...201627604468
high ifn-γ release and impaired capacity of multi-cytokine secretion in igra supernatants are associated with active tuberculosis.interferon gamma (ifn-γ) release assays (igras) detect mycobacterium tuberculosis (mtb) infection regardless of the active (atb) or latent (ltbi) forms of tuberculosis (tb). in this study, mtb-specific t cell response against region of deletion 1 (rd1) antigens were explored by a microbead multiplex assay performed in t-spot tb assay (t-spot) supernatants from 35 patients with atb and 115 patients with ltbi. t-spot is positive when over 7 ifn-γ secreting cells (sc)/250 000 peripheral blood monon ...201627603919
investigating the reaction mechanism of f420-dependent glucose-6-phosphate dehydrogenase from mycobacterium tuberculosis: kinetic analysis of the wild-type and mutant enzymes.f420-dependent glucose-6-phosphate dehydrogenase (fgd) catalyzes the conversion of glucose-6-phosphate (g6p) to 6-phosphogluconolactone, using f420 cofactor as the hydride transfer acceptor, within mycobacteria. a previous crystal structure of wild-type fgd led to a proposed mechanism suggesting that the active site residues his40, trp44, and glu109 could be involved in catalysis. we have characterized the wild-type fgd and five fgd variants (h40a, w44f, w44y, w44a, and e109q) by fluorescence bi ...201627603793
design, synthesis, and characterization of (1-(4-aryl)- 1h-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against mycobacterium tuberculosis.the novel (1-(4-aryl)-1h-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of cu(oac)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. the newly synthesized compounds were characterized by a number of spectroscopic techniques, ...201627601885
bis-biguanide dihydrochloride inhibits intracellular replication of m. tuberculosis and controls infection in mice.while there is an urgent need to develop new and effective drugs for treatment of tuberculosis (tb) and multi-drug resistant tb (mdr-tb), repurposing fda (u.s. food and drug administration) -approved drugs for development of anti-tb agents may decrease time and effort from bench to bedside. here, we employed host cell-based high throughput screening (hts) assay to screen and characterize fda-approved, off-patent library drugs for anti-mycobacterium tuberculosis (mtb) activities. the cell-based h ...201627601302
pyrazinamide resistance assays and two-month sputum culture status in patients with multidrug-resistant tuberculosis.phenotypic drug susceptibility testing is the current "gold standard" for detecting mycobacterium tuberculosis susceptibility to antituberculous drugs. pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. here we performed latent class analysis (lca) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. we then compared this consensus m ...201627600032
culture and reverse transcriptase polymerase chain reaction (rt-pcr) proven mycobacterium tuberculosis endophthalmitis: a case series.to report early confirmation of mycobacterium tuberculosis (mtb) endophthalmitis by detection of 85b mrna in vitreous by a reverse transcriptase polymerase chain reaction (rt-pcr) technique.201627598944
[spondylodiscitis: clinical experience in a chilean general hospital].spondylodiscitis (sd) involves long periods of hospitalization, diagnostic latency and risk of long-term complications. no updated series are available in chile and a change in demographic features and etiology is suspected.201627598284
identification of secretory proteins in mycobacterium tuberculosis using pseudo amino acid composition.tuberculosis is killing millions of lives every year and on the blacklist of the most appalling public health problems. recent findings suggest that secretory protein of mycobacterium tuberculosis may serve the purpose of developing specific vaccines and drugs due to their antigenicity. responding to global infectious disease, we focused on the identification of secretory proteins in mycobacterium tuberculosis. a novel method called mycosec was designed by incorporating g-gap dipeptide compositi ...201627597968
persisting positron emission tomography lesion activity and mycobacterium tuberculosis mrna after tuberculosis cure.the absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (ptb). we detected positron emission tomography and computerized tomography (pet-ct) imaging response patterns consistent with active disease, along with the presence of mycobacterium tuberculosis (mtb) mrna in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, hiv-negative patients with ptb after a s ...201627595324
antibiotic methylation: a new mechanism of antimicrobial resistance.in new research on mycobacterium tuberculosis, the causative agent of tuberculosis, warrier and colleagues have discovered a novel mode of bacterial drug resistance, namely antibiotic inactivation via n-methylation.201627593675
strategies to enhance immunogenicity of cdna vaccine encoded antigens by modulation of antigen processing.most vaccines are based on protective humoral responses while for intracellular pathogens cd8(+) t cells are regularly needed to provide protection. however, poor processing efficiency of antigens is often a limiting factor in cd8(+) t cell priming, hampering vaccine efficacy. the multistage cdna vaccine h56, encoding three secreted mycobacterium tuberculosis antigens, was used to test a complete strategy to enhance vaccine' immunogenicity. potential cd8(+) t cell epitopes in h56 were predicted ...201627593157
immune response to mycobacterium tuberculosis in young contacts with discordant immunological test results. 201627592265
synthesis and evaluation of copper(ii) complexes with isoniazid-derived hydrazones as anticancer and antitubercular agents.in this study, the n,n,o metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (hpcih, 1) and its derivatives 2-acetylpyridine-(hapih 2), 2-pyridineformamide-(hpamih, 3) and pyrazineformamide-(hpzamih, 4) were employed in the synthesis of four copper(ii) complexes, [cu(hpcih)cl2]·0.4h2o (5), [cu(hapih)cl2]·1.25h2o (6), [cu(hpamih)cl2]·h2o (7) and [cu(hpzamih)cl2]·1.25h2o (8). the compounds were assayed for their action toward mycobacterium tuberculosis h37rv atcc 27294 strain and the hu ...201627591998
virtual screening and x-ray crystallography identify non-substrate analog inhibitors of flavin-dependent thymidylate synthase.thymidylate synthase x (thyx) represents an attractive target for tuberculosis drug discovery. herein, we selected 16 compounds through a virtual screening approach. we solved the first x-ray crystal structure of thermatoga maritima (tm) thyx in complex with a nonsubstrate analog inhibitor. given the active site similarities between mycobacterium tuberculosis thyx (mtb-thyx) and tm-thyx, our crystal structure paves the way for a structure-based design of novel antimycobacterial compounds. the 1h ...201627589670
identifying components for programmatic latent tuberculosis infection control in the european union.individuals with latent tuberculosis infection (ltbi) are the reservoir of mycobacterium tuberculosis in a population and as long as this reservoir exists, elimination of tuberculosis (tb) will not be feasible. in 2013, the european centre for disease prevention and control (ecdc) started an assessment of benefits and risks of introducing programmatic ltbi control, with the aim of providing guidance on how to incorporate ltbi control into national tb strategies in european union/european economi ...201627589214
necrotic cell sensor clec4e promotes a proatherogenic macrophage phenotype through activation of the unfolded protein response.atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. c-type lectin receptor 4e (clec4e) recognizes the cord factor of mycobacterium tuberculosis but also senses molecular patterns rel ...201627587433
analysis of the contribution of mtp and the predicted flp pilus genes to mycobacterium tuberculosis pathogenesis.mycobacterium tuberculosis (mtb) is one of the world's most successful pathogens. millions of new cases of tuberculosis occur each year, emphasizing the need for better methods of treatment. the design of novel therapeutics is dependent on our understanding of factors that are essential for pathogenesis. many bacterial pathogens use pili and other adhesins to mediate pathogenesis. the recently identified mycobacterium tuberculosis pilus (mtp) and the hypothetical, widely conserved flp pilus have ...201627586540
enhanced immune response of mait cells in tuberculous pleural effusions depends on cytokine signaling.the functions of mait cells at the site of mycobacterium tuberculosis infection in humans are still largely unknown. in this study, the phenotypes and immune response of mait cells from tuberculous pleural effusions and peripheral blood were investigated. mait cells in tuberculous pleural effusions had greatly enhanced ifn-γ, il-17f and granzyme b response compared with those in peripheral blood. the level of ifn-γ response in mait cells from tuberculous pleural effusions was inversely correlate ...201627586092
the genotypic study of mycobacterium tuberculosis complex resistant to isoniazid: galicia, spain (2008-2013).incorporation of rapid detection systems to identify mutations in m. tuberculosis complex that confer resistance to isoniazid and rifampicin has potentiated the knowledge of their distribution, given the geographical variability. we performed antibiograms of the 2,993 strains isolated in galicia, spain (2008-2013). in the strains resistant to isoniazid, a concentration of 0.4 mg/ml and mtbdrplus genotype test (hain lifescience, germany) were used. we found that 3.64 % of strains were resistant t ...201627586016
microwave-assisted synthesis of 2-styrylquinoline-4-carboxylic acids as antitubercular agents.many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies.201627585570
effects of mbl-associated serine protease-2 (masp-2) on liquefaction and ulceration in rabbit skin model of tuberculosis.tuberculosis is a chronic infectious disease, which caused by mycobacterium tuberculosis. it typically affects the functions of the lung and causes high morbidity and mortality rates worldwide. the lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. however, what is the specific effection between tuberculosis and complement is unknown. mannose-binding lectin (mbl), a recognition subunit, binds to arrays of carbohydrates on the s ...201627585546
drug susceptibility patterns of the mycobacterium tuberculosis isolated from previously treated and new cases of pulmonary tuberculosis at german-nepal tuberculosis project laboratory, kathmandu, nepal.multidrug resistant tuberculosis (mdr-tb) is a serious public health problem in nepal. it is a major obstacle for the control of the tuberculosis. the main objectives of this study were to determine the prevalence of the multidrug resistant pulmonary tuberculosis and to evaluate the drug susceptibility patterns of mycobacterium tuberculosis isolated from previously treated and newly diagnosed cases of pulmonary tuberculosis.201627583136
[tuberculous pyopneumothorax: about 18 cases].tuberculous pyopneumothorax is a rare but serious complication of evolutive pulmonary tuberculosis. we report a series of 18 cases with tuberculous pyopneumothorax admitted to the pneumo-phthisiology department of the mohammed v military teaching hospital in rabat between january 2005 and december 2009. our study included 15 men and 3 women, the average age was 35 ± 7 years. 4 patients were diabetic. smoking was found in 9 cases. right-sided pneumothorax was found in 13 cases. chest radiograph s ...201627583090
patterns of drug resistance among tuberculosis patients in west and northwestern iran.tuberculosis (tb) is the leading cause of morbidity and mortality among chronic infectious diseases.201627583054
insights into horizontal acquisition patterns of dormancy and reactivation regulon genes in mycobacterial species using a partitioning-based framework.horizontal gene transfer (hgt) events, initially thought to be rare in mycobacterium tuberculosis, have recently been shown to be involved in the acquisition of virulence operons in m. tuberculosis. we have developed a new partitioning framework based hgt prediction algorithm, called grid3m, and applied the same for the prediction of hgts in mycobacteria. validation and testing using simulated and real microbial genomes indicated better performance of grid3m as compared with other widely used hg ...201627581938
smear positive pulmonary tuberculosis and associated factors among homeless individuals in dessie and debre birhan towns, northeast ethiopia.tuberculosis (tb) remains one of the globe's deadliest communicable diseases. the homeless individuals are at high risk to acquire tb and multi-drug resistant tb (mdr-tb), because of their poor living conditions and risky behaviors. tuberculosis and mdr-tb in the homeless individuals can pose a risk to entire communities. however, the magnitude of the problem is not known in ethiopia. therefore, the aim of this study was to determine the prevalence and associated factors of smear positive pulmon ...201627581729
identification of kasa as the cellular target of an anti-tubercular scaffold.phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. in this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (gsk3011724a) identifies several specific single-nucleotide polymorphisms in the essential mycobacterium tuberculosis β-ketoacyl synthase (kas) a gene. here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of ...201627581223
ifn-γ release assay result is associated with disease site and death in active tuberculosis.the ifn-γ release assays and tuberculin skin tests are used to support the diagnosis of both latent and active tuberculosis. however, we previously demonstrated that a negative tuberculin test in active tuberculosis is associated with disseminated disease and death. it is unknown whether the same associations exist for ifn-γ release assays.201627580246
propargyl-linked antifolates are potent inhibitors of drug-sensitive and drug-resistant mycobacterium tuberculosis.mycobacterium tuberculosis continues to cause widespread, life-threatening disease. in the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (mdr and xdr) bacteria have spread globally and the number of agents that effectively treat these infections is significantly reduced. we have been developing the propargyl-linked antifolates (plas) as potent inhibitors of the essential enzyme dihydrofolate reductase (dhfr) from bacteria and recently found that charged ...201627580226
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