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rational design of drug-like compounds targeting mycobacterium marinum melf protein.the mycobacterial mel2 locus (mycobacterial enhanced infection locus, rv1936-1941) is mycobacterium marinum and m. tuberculosis specific, which can withstand reactive oxygen species (ros) and reactive nitrogen species (rns) induced stress. a library of over a million compounds was screened using in silico virtual ligand screening (vls) to identify inhibitors against the modeled structure of melf protein expressed by melf of mel2 locus so that m. marinum's ability to withstand ros/rns stress coul ...201728873466
a new cinnamic acid derivative from plant-derived endophytic fungus pyronema sp.ten secondary metabolites (1-10) including a new 4-hydroxycinnamic acid derivatives, methyl 2-{(e)-2-[4-(formyloxy)phenyl]ethenyl}-4-methyl-3-oxopentanoate (1), and nine known compounds (2-10) were isolated from an etoac extract derived from a solid rice medium of endophytic fungal strain pyronema sp. (a2-1 & d1-2). their structures were elucidated from nmr and hrms data. all the compounds were tested for antibacterial activity against mycobacterium marinum atccbaa-535. compounds 1, 8 and 9 exhi ...201728391728
inhibitors of mycobacterium marinum virulence identified in a dictyostelium discoideum host model.tuberculosis remains one of the major threats to public health worldwide. given the prevalence of multi drug resistance (mdr) in mycobacterium tuberculosis strains, there is a strong need to develop new anti-mycobacterial drugs with modes of action distinct from classical antibiotics. inhibitors of mycobacterial virulence might target new molecular processes and may represent a potential new therapeutic alternative. in this study, we used a dictyostelium discoideum host model to assess virulence ...201728727774
spatio-temporal study of environmental nontuberculous mycobacteria isolated from wardha district in central india.during the last two decades, nontuberculous mycobacteria (ntm) have gained in importance but there is still a paucity of data, particularly for environmental isolates. we studied, over a period of two years, the spatio-temporal features of ntm isolates obtained from different environmental sources in wardha district, india. a total of 1398 samples (699 each of soil and water) were tested and 170 (12.2%) yielded ntm isolates, including 123 from soil and 47 from water samples. out of 170 ntm isola ...201728836034
the impact of genome region of difference 4 (rd4) on mycobacterial virulence and bcg efficacy.comparative genome analyses have revealed a number of regions of difference (rd) among mycobacterial species. the functional consequences of most of these genome variations have not been studied. rd4, which encompasses rv1506c-rv1516c of mycobacterium tuberculosis (m. tb) h37rv, is absent in the closely related mycobacterium bovis and m. bovis bacille calmette-guérin (bcg). on the other hand, we previously found that mycobacterium marinum has an extended rd4 which includes a number of genes invo ...201728642843
efficacy of calcium hypochlorite and ultraviolet irradiation against mycobacterium fortuitum and mycobacterium marinum.nontuberculous mycobacteria (ntm) cause opportunistic infections with increasing frequency in immunocompromised humans. water is one of the natural sources for transmission of ntm and plays a major role in the epidemiology of ntm infections. this study evaluated the efficacy of calcium hypochlorite and ultraviolet irradiation (uv) to eliminate potentially zoonotic ntm species such as m. marinum and m. fortuitum.201728776533
acid-fast bacterium detection and identification from paraffin-embedded tissues using a pcr-pyrosequencing method.acid-fast bacterium (afb) identification from formalin-fixed paraffin-embedded (ffpe) tissues is challenging and may not be readily available to the clinical laboratory. a method to detect and identify afb from ffpe tissues using pcr and pyrosequencing (pcr-seq) was developed and evaluated.201728735303
in silico prediction of antibiotic resistance in mycobacterium ulcerans agy99 through whole genome sequence analysis.buruli ulcer is an emerging infectious disease caused by mycobacterium ulcerans that has been reported from 33 countries. antimicrobial agents either alone or in combination with surgery have been proved to be clinically relevant and therapeutic strategies have been deduced mainly from the empirical experience. the genome sequences of m. ulcerans strain agy99, m. ulcerans ecovar liflandii, and three mycobacterium marinum strains were analyzed to predict resistance in these bacteria. fourteen put ...201728749770
microbial offense vs host defense: who controls the tb granuloma?the granuloma is the hallmark of tuberculosis and simultaneously signifies acquisition of an infection and induction of a host immune response. but who benefits more from the development of the granuloma, the host or the pathogen? is microbe or man dictating disease course and progression? mycobacterial diseases affect humans and animals alike, and the concepts presented in this review reflect host-pathogen interactions that influence not only mycobacterial granulomas in humans and animals but a ...201728749750
active nuclear transcriptome analysis reveals inflammasome-dependent mechanism for early neutrophil response to mycobacterium marinum.the mechanisms governing neutrophil response to mycobacterium tuberculosis remain poorly understood. in this study we utilise biotagging, a novel genome-wide profiling approach based on cell type-specific in vivo biotinylation in zebrafish to analyse the initial response of neutrophils to mycobacterium marinum, a close genetic relative of m. tuberculosis used to model tuberculosis. differential expression analysis following nuclear rna-seq of neutrophil active transcriptomes reveals a significan ...201728747644
identification of novel antigen candidates for a tuberculosis vaccine in the adult zebrafish (danio rerio).tuberculosis (tb) remains a major global health challenge and the development of a better vaccine takes center stage in fighting the disease. for this purpose, animal models that are capable of replicating the course of the disease and are suitable for the early-stage screening of vaccine candidates are needed. a mycobacterium marinum infection in adult zebrafish resembles human tb. here, we present a pre-clinical screen for a dna-based tuberculosis vaccine in the adult zebrafish using an m. mar ...201728742838
translocation of nanoparticles and mycobacterium marinum across the intestinal epithelium in zebrafish and the role of the mucosal immune system.nano- and microparticles are promising carrier systems for oral delivery of drugs or vaccines, particularly in fish aquaculture. however, the mechanisms of uptake, trans-epithelial transport and immune response to nano/micrometer sized particles, or microorganisms such as bacteria are poorly understood in fish. here, adult zebrafish were used to study the uptake of different nano- and microparticles and the pathogenic bacteria mycobacterium marinum in the intestine, and their interactions with e ...201727343826
murine mycobacterium marinum infection as a model for tuberculosis.mycobacteria are a major human health problem globally. regarding tuberculosis the situation is worsened by the poor efficacy of current vaccine regimens and by emergence of drug-resistant strains (manjelievskaia j et al, trans r soc trop med hyg 110: 110, 2016; pereira et al., lancet infect dis 12:300-306, 2012; http://www.who.int/tb/publications/global_report/en/) undermining both disease-prevention and available treatments. thus, increased basic understanding of mycobacterial-and particularly ...201727914088
the inflammatory chemokine cxcl18b exerts neutrophil-specific chemotaxis via the promiscuous chemokine receptor cxcr2 in zebrafish.cxcl18b is a chemokine found in zebrafish and in other piscine and amphibian species. cxcl18b is a reliable inflammatory marker; however, its function is yet to be elucidated. here, we found that cxcl18b is chemotactic towards neutrophils, similarly to cxcl8a/interleukin-8, the best characterised neutrophil chemoattractant in humans and teleosts. like cxcl8a, cxcl18b-dependent recruitment required the chemokine receptor cxcr2, while it was unaffected by depletion of the other two neutrophil rece ...201727815178
screening of anti-mycobacterial compounds in a naturally infected zebrafish larvae model.mycobacterium tuberculosis is a deadly human pathogen that causes the lung disease tb. m. tuberculosis latently infects a third of the world's population, resulting in ∼1.5 million deaths per year. due to the difficulties and expense of carrying out animal drug trials using m. tuberculosis and rodents, infections of the zebrafish danio rerio with mycobacterium marinum have become a useful surrogate. however, the infection methods described to date require specialized equipment and a high level o ...201727798206
a nonsense mutation in mycobacterium marinum that is suppressible by a novel mechanism.mycobacterial pathogens use the esat-6 system 1 (esx-1) exporter to promote virulence. previously, we used gene disruption and complementation to conclude that the mmar_0039 gene in mycobacterium marinum is required to promote esx-1 export. here we applied molecular genetics, proteomics, and whole-genome sequencing to demonstrate that the mmar_0039 gene is not required for esx-1 secretion or virulence. these findings suggest that we initially observed an indirect mechanism of genetic complementa ...201727789543
mycobacteriosis caused by mycobacterium marinum in reared mullets: first evidence from sardinia (italy).mycobacterium marinum is a slow-growing non-tuberculous mycobacterium, and it is considered the most common aetiologic agent of mycobacteriosis in wild and cultured fish. the diagnosis is principally made by histology when positive ziehl-neelsen stain granulomas are detected. the aim of this study was to investigate the occurrence of mycobacteriosis in extensively cultured mugilidae of two lagoons (cabras and san teodoro) from sardinia by the use of histology, microbiology, pcr and dna sequencin ...201727368155
mycobacterium marinum.mycobacterium marinum is a well-known pathogenic mycobacterium for skin and soft tissue infections and is associated with fishes and water. among nontuberculous mycobacteria (ntm), it is the leading cause of extrarespiratory human infections worldwide. in addition, there is a specific scientific interest in m. marinum because of its genetic relatedness to mycobacterium tuberculosis and because experimental infection of m. marinum in fishes mimics tuberculosis pathogenesis. microbiological charac ...201728387180
chronic cutaneous mycobacterial ulcers due to mycobacterium ulcerans (buruli ulcer): the first indigenous case report from jordan and a literature review.buruli ulcer is the third most common mycobacterial infection worldwide. it is endemic in tropical, subtropical, and temperate climates. it causes devastating disease with morbidity and mortality. the treatment duration is long and the regimens considered are limited. chronic cutaneous ulcers of mycobacterial etiology have been reported previously in amman, but these were not associated with mycobacterium ulcerans infection.201728344056
the chemokine receptor cxcr4 promotes granuloma formation by sustaining a mycobacteria-induced angiogenesis programme.cxc chemokine receptor 4 plays a critical role in chemotaxis and leukocyte differentiation. furthermore, there is increasing evidence that links this receptor to angiogenesis. using the well-established zebrafish-mycobacterium marinum model for tuberculosis, angiogenesis was recently found to be important for the development of cellular aggregates called granulomas that contain the mycobacteria and are the hallmark of tuberculosis disease. here, we found that initiation of the granuloma-associat ...201728332618
[nontuberculous mycobacteria].dermatologically relevant nontuberculous mycobacteria (ntm) include mycobacterium marinum and mycobacterium ulcerans and different rapidly growing mycobacteria (rgm). rgm are widely present in the environment and are facultative pathogenic. diagnostic detection of nontuberculous mycobacteria is frequently challenging. immune-competent individuals mostly develop localized infections. immune-suppressed patients may present with severe and disseminated disease. in these cases, rapid initiation of m ...201728331949
mycolactone-producing mycobacterium marinum infection in captive hong kong warty newts and pathological evidence of impaired host immune function.a mass mortality event of captive hong kong warty newts paramesotriton hongkongensis with non-granulomatous necrotic lesions occurred in taipei zoo, taiwan, in 2014. clinically, the sick newts were lethargic and often covered with water mold saprolegnia sp. on the skin of the body trunk or extremities. predominant pathological findings were multifocal non-granulomatous necrotic lesions in the liver, spleen, and kidneys and severe skin infection with saprolegnia sp., with deep invasion and involv ...201728322210
dynamic regulation of fatty acid pools for improved production of fatty alcohols in saccharomyces cerevisiae.in vivo production of fatty acid-derived chemicals in saccharomyces cerevisiae requires strategies to increase the intracellular supply of either acyl-coa or free fatty acids (ffas), since their cytosolic concentrations are quite low in a natural state for this organism. deletion of the fatty acyl-coa synthetase genes faa1 and faa4 is an effective and straightforward way to disable re-activation of fatty acids and drastically increase ffa levels. however, this strategy causes ffa over-accumulati ...201728298234
regulation of phagocyte triglyceride by a stat-atg2 pathway controls mycobacterial infection.mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. here we show that cytokine-stat signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via atg2 repression. in drosophila infected with mycobacterium marinum ...201728262681
functional characterisation of the drosophila cg6568 gene in host defence against mycobacterium marinum.mycobacterium marinum is a pathogenic mycobacterial species closely related to mycobacterium tuberculosis. in this study, we established a mycobacterial infection model of drosophila melanogaster to characterize the role played by cg6568, a homolog of the human cathelicidin gene, in the innate defense against infection. drosophila cg6568 was expressed at various levels during all developmental stages, and the expression levels were modulated by m. marinum in a time-dependent manner. 20-hydroxyec ...201728245983
effectiveness of purified methylene blue in an experimental model of mycobacterium ulcerans infection.mycobacterium ulcerans is responsible for buruli ulcer, characterised by extensive, disabling ulcers. standard treatment combining rifampicin and streptomycin exposes patients to toxicity and daily painful injections. in this study, the in vitro susceptibilities of 3 m. ulcerans strains, 1 mycobacterium marinum strain and 18 strains representative of eleven other mycobacterium species and subspecies to methylene blue were determined. whilst growth of m. ulcerans was inhibited by 0.0125 g/l methy ...201728131607
mycobacterial esx-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions.mycobacterium tuberculosis and mycobacterium marinum are thought to exert virulence, in part, through their ability to lyse host cell membranes. the type vii secretion system esx-1 [6-kda early secretory antigenic target (esat-6) secretion system 1] is required for both virulence and host cell membrane lysis. both activities are attributed to the pore-forming activity of the esx-1-secreted substrate esat-6 because multiple studies have reported that recombinant esat-6 lyses eukaryotic membranes. ...201728119503
high-throughput carbon substrate profiling of mycobacterium ulcerans suggests potential environmental reservoirs.mycobacterium ulcerans is a close derivative of mycobacterium marinum and the agent of buruli ulcer in some tropical countries. epidemiological and environmental studies pointed towards stagnant water ecosystems as potential sources of m. ulcerans, yet the ultimate reservoirs remain elusive. we hypothesized that carbon substrate determination may help elucidating the spectrum of potential reservoirs.201728095422
mycobacterium tuberculosis and mycobacterium marinum non-homologous end-joining proteins can function together to join dna ends in escherichia coli.mycobacterium tuberculosis and mycobacterium smegmatis express a ku protein and a dna ligase d and are able to repair dna double strand breaks (dsbs) by non-homologous end-joining (nhej). this pathway protects against dna damage when bacteria are in stationary phase. mycobacterium marinum is a member of this mycobacterium family and like m. tuberculosis is pathogenic. m. marinum lives in water, forms biofilms and infects fish and frogs. m. marinum is a biosafety level 2 (bsl2) organism as it can ...201727613236
mycobacterium marinum degrades both triacylglycerols and phospholipids from its dictyostelium host to synthesise its own triacylglycerols and generate lipid inclusions.during a tuberculosis infection and inside lipid-laden foamy macrophages, fatty acids (fas) and sterols are the major energy and carbon source for mycobacterium tuberculosis. mycobacteria can be found both inside a vacuole and the cytosol, but how this impacts their access to lipids is not well appreciated. lipid droplets (lds) store fas in form of triacylglycerols (tags) and are energy reservoirs of prokaryotes and eukaryotes. using the dictyostelium discoideum/mycobacterium marinum infection m ...201728103313
recombinant bcg expressing esx-1 of mycobacterium marinum combines low virulence with cytosolic immune signaling and improved tb protection.recent insights into the mechanisms by which mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. the only licensed anti-tuberculosis vaccine, mycobacterium bovis bcg, provides limited protection. a feature of bcg is the partial deletion of the esx-1 type vii secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked t ...201728297677
atypical mycobacterial infections of the upper extremity: becoming more atypical?background: atypical mycobacterial infections are uncommon and characterized by a chronic, indolent course before diagnosis. historically, these infections are associated with marine-related injury and/or immune dysfunction. our institution has successfully diagnosed and treated an increasing number of these infections. the objective of this study is to review our experience with these rare infections and verify the developing trends encountered. methods: a retrospective review was performed for ...201728344532
emerging causes of superficial and invasive infections following marine injuries and exposures.soft tissue bacterial infections following aquatic animal bites, stings, and minor injuries occur commonly and usually on the extremities in fishermen and beachgoers worldwide after freshwater and saltwater exposures. louisiana has more tidal, saltwater, and brackish water shorelines (more than 7,000 miles) than any other state, including alaska and hawaii. as a result, louisiana residents are often exposed to marine pathogens when fishing or working offshore or when enjoying louisiana's miles o ...201725075726
buruli ulcer, a prototype for ecosystem-related infection, caused by mycobacterium ulcerans.buruli ulcer is a noncontagious disabling cutaneous and subcutaneous mycobacteriosis reported by 33 countries in africa, asia, oceania, and south america. the causative agent, mycobacterium ulcerans, derives from mycobacterium marinum by genomic reduction and acquisition of a plasmid-borne, nonribosomal cytotoxin mycolactone, the major virulence factor. m. ulcerans-specific sequences have been readily detected in aquatic environments in food chains involving small mammals. skin contamination com ...201829237707
structural and functional characterisation of the cytochrome p450 enzyme cyp268a2 from mycobacterium marinum.members of the cytochrome p450 monooxygenase family cyp268 are found across a broad range of mycobacterium species including the pathogens mycobacterium avium, m. colombiense,m. kansasii and mmarinum cyp268a2, from m. marinum , which is the first member of this family to be studied, was purified and characterised. cyp268a2 was found to bind a variety of substrates with high affinity, including branched and straight-chain fatty acids (c10-c12), acetate esters, and aromatic compounds. the enzyme w ...201829343612
mycobacterium marinum infection in zebrafish and microglia imitates the early stage of tuberculous meningitis.mycobacterium tuberculosis (m. tuberculosis) invading and activating microglia causes the most serious subtypes of tuberculosis called tubercular meningitis. however, the developmental process of tubercular meningitis, especially the early phase, is poorly understood due to lacking well-established and well-accepted visible models in vitro and in vivo. here, consistent with one recent report, we found mycobacterium marinum (m. marinum) invade the zebrafish brain and subsequently cause granuloma- ...201829352446
using rt qpcr for quantifying mycobacteria marinum from in vitro and in vivo samples.mycobacterium marinum, the causative agent of fish tuberculosis, is rarely a human pathogen causing a chronic skin infection. it is now wildely used as a model system in animal models, especially in zebra fish model, to study the pathology of tuberculosis and as a means of screening new anti-tuberculosis agent. to facilitate such research, quantifying the viable count of m. marinum bacteria is a crucial step. the main approach used currently is still by counting the number of colony forming unit ...201829322466
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