Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phagocytosis with macrophages provides a specialized mechanism for regulated ingestion and intracellular destruction of bacteria. Bacteria are first engulfed by endocytosis into a phagosome. The fusion of phagosomes and lysosomes releases toxic products that kill most bacteria and degrade them into fragments. Debris from dead bacteria is then released by exocytosis. However, some bacteria that survive within host phagocytes have evolved strategies to escape the bactericidal mechanisms associated with phagocytosis: i) antiphagocytosis (Yersinia), ii) escaping from the phagosome into cytoplasm (Listeria), and iii) remodeling their phagosome by inhibiting the maturation of phagosomes (Salmonella, Mycobacterium, Legionella). In this review, I first summarize various strategies by bacteria to avoid phagocytosis by emphasizing the steps that have been subverted by bacteria. Then, I highlight the mechanisms for surviving phagocytosis by Salmonella, with a focus on the induction of macrophage-apoptosis and modulation of membrane traffic in host cells.
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PMID:[Bacterial strategies for escaping the bactericidal mechanisms by macrophage]. 1713 49

Diverse aspects of host-pathogen interactions have been studied using non-mammalian hosts such as Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio for more than 20 years. Over the past two years, the use of these model hosts to dissect bacterial virulence mechanisms has been expanded to include the important human pathogens Vibrio cholerae and Yersinia pestis. Innovative approaches using these alternative hosts have also been developed, enabling the isolation of new antimicrobials through screening large libraries of compounds in a C. elegans Enterococcus faecalis infection model. Host proteins required by Mycobacterium and Listeria during their invasion and intracellular growth have been uncovered using high-throughput dsRNA screens in a Drosophila cell culture system, and immune evasion mechanisms deployed by Pseudomonas aeruginosa during its infection of flies have been identified. Together, these reports further illustrate the potential and relevance of these non-mammalian hosts for modelling many facets of bacterial infection in mammals.
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PMID:Infection in a dish: high-throughput analyses of bacterial pathogenesis. 1717 62

The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.
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PMID:Targeting the methyl erythritol phosphate (MEP) pathway for novel antimalarial, antibacterial and herbicidal drug discovery: inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) enzyme. 1743 Jan 77

Human Vgamma2Vdelta2 T cells are stimulated by prenyl pyrophosphates, such as isopentenyl pyrophosphate (IPP), and play important roles in mediating immunity against microbial pathogens and have potent anti-tumor activity. (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) has been identified as a metabolite in the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway for isoprenoid biosynthesis that is used by many bacteria and protozoan parasites. We find that HMBPP is the major Vgamma2Vdelta2 T-cell antigen for many bacteria, including Mycobacterium tuberculosis, Yersinia enterocolitica and Escherichia coli. HMBPP was a 30 000-fold more potent antigen than IPP. Using mutant bacteria, we show that bacterial antigen levels for Vgamma2Vdelta2 T cells are controlled by MEP pathway enzymes and find no evidence for the production of 3-formyl-1-butyl pyrophosphate. Moreover, HMBPP reactivity required only germ line-encoded Vgamma2Vdelta2 TCR elements and is present at birth. Importantly, we show that bacterial HMBPP levels correlated with their ability to expand Vgamma2Vdelta2 T cells in vivo upon engraftment into severe combined immunodeficiency-beige mice. Thus, the production of HMBPP by a microbial-specific isoprenoid pathway plays a major role in determining whether bacteria will stimulate Vgamma2Vdelta2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite allows Vgamma2Vdelta2 T cells to respond to a broad array of pathogens using this pathway.
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PMID:Preferential recognition of a microbial metabolite by human Vgamma2Vdelta2 T cells. 1744 9

In molecular diagnosis of infectious diseases often more than 1 pathogen has to be considered. As a consequence, a series of labor-intensive and time-consuming polymerase chain reaction (PCR) approaches specific for different putative pathogens have to be carried out. To speed up diagnosis, we established a low-density microarray for simultaneous detection of diverse putative pathogens causing a disease such as granulomatous lymphadenitis. Nucleic acids from formalin-fixed, paraffin-embedded tissues of 68 patients with lymphadenitis were used for molecular diagnosis of individual pathogens by either nested single-assay PCR or 1-step multiplex PCR in combination with low-density microarray hybridization. Multiplex PCR amplicons hybridized to glass slides containing probes from Mycobacterium spp., Yersinia spp., Bartonella henselae, Toxoplasma gondii, and other pathogens showed specific and reproducible signals on the array. Our results show that microarray technology combined with multiplex PCR is a promising and time-saving tool in molecular pathology of infectious diseases, allowing sensitive, simultaneous analyses of different pathogens.
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PMID:Detection of opportunistic infections by low-density microarrays: a diagnostic approach for granulomatous lymphadenitis. 1747 Nov 54

The numbers of global infections produced by bacterial strains that are resistant to single and multiple antimicrobial drugs are on the rise. Concomitant with this alarming upward trend, there is a clear downward trend in the intent and determination of pharmaceutical companies to develop novel antimicrobials. One of the pressing goals to confront the twenty first century's public health challenges brought about by the escalating antibacterial drug resistance problem is the development of an armamentarium of new chemotherapeutic agents. Two interconnected strategic paradigm shifts in the drug discovery process that are anticipated to facilitate the achievement of this goal are discussed herein. One is an antimicrobial to anti-infective (ATA) paradigm shift. The other is a shift from a target candidate prioritization (TCP) paradigm that is dominated by an essential target preference criterion to an alternative paradigm that relies on a less restrictive criterion, one that does not exclude conditionally essential targets. Examples of conditionally essential targets for the development of anti infectives include the enzymes involved in the biosynthesis of small molecule virulence effectors such as non ribosomal peptide polyketide derived iron scavenging siderophores. Siderophores are utilized for iron uptake by many pathogenic bacteria, including Mycobacterium and Yersinia species. The recent progress towards developing inhibitors of siderophore biosynthesis is discussed herein.
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PMID:Strategic paradigm shifts in the antimicrobial drug discovery process of the 21st century. 1789 59

Bacteria utilise Twin arginine translocation (Tat) to deliver folded proteins across the cytoplasmic membrane. Disruption of Tat typically results in pleiotropic effects on e.g. growth, stress resistance, bacterial membrane biogenesis, motility and cell morphology. Further, Tat is coupled to virulence in a range of pathogenic bacteria, including species of Pseudomonas, Legionella, Agrobacterium and Mycobacterium. We have investigated this, for Yersinia, previously unexplored system, and have shown that the Tat pathway is functional and absolutely required for virulence of Yersinia pseudotuberculosis. A range of putative Yersinia Tat substrates have been predicted in silico, which together with the Tat system itself may be interesting targets for future development of antimicrobial treatments. Here we present a brief review of bacterial Tat and discuss our results concerning this system in Yersinia.
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PMID:Twin arginine translocation in Yersinia. 1796 22

The emergence of pathogens is the result of a number of impact in all parts of the food chain. The emerging technologies in food production explain how new pathogens can establish themselves in the food chain and compromise food safety. The impact of the food technology is analysed for several bacteria, such as Yersinia, Campylobacter, Arcobacter, Helicobacter pullorum, Enterobacter sakazakii, Mycobacterium avium spp. paratuberculosis, prions related to vCJD and others. The importance of the ability of many microbes to form VBNC forms is elaborated on. Research on culture independent methods may address this outstanding issue to the better understanding of emerging pathogens. The "demerging" of pathogens also occur, and examples of this are explained. The reaction of bacteria to stresses and sublethal treatments, and how exposure to one stress factor can confer resistance to other stresses, literally speaking causing contagious resistance, are explained. The implication of this e.g. in modern approaches of food preservation, such as Minimally processed Foods, is considerable. Intestinal colonization of EHEC may be regulated by Quorum sensing, and this ability of microbes plays an important role in the colonization of microbes in food and on food processing equipment, an important factor in the emergence of pathogens. The emergence of Saccharomyces cerevisiae, as an opportunistic human pathogen, used for centuries for food and production of alcoholic beverages, calls for research in molecular tools to distinguish between probiotic and clinical strains. Cyclospora cayetanensis and Norovirus outbreaks can no longer be designated as emerging pathogens, they share however one characteristic in the epidemiology of emerging nature, the importance of the hygiene in the primary production stage, including supply of potable water, and the application of GMP and the HACCP principles in the beginning of the food chain. Hepatitis E virus is a potential emerging food borne pathogen and swine may serve as a source of infection in human, a most challenging issue in greater part of the world raising pigs. Tick-borne encephalitis virus infection, either thick borne or caused by consumption of raw milk, is an increasing trend in the industrialized part of the world. Consumer awareness, ethics of food, sustainability in food production, and trust in foods, are of growing importance to the consumer. The reaction of the consumer to new technology, such as nanotechnology, is unpredictable. Many efforts should be devoted to communication of non-biased information to both the food producers as well as the consumer.
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PMID:New trends in emerging pathogens. 1797 49

Foodborne zoonoses have a major health impact in industrialised countries. New European food safety regulations were issued to apply risk analysis to the food chain. The severity of foodborne zoonoses and the exposure of humans to biological hazards transmitted by food must be assessed. For meat, inspection at the slaughterhouse is historically the main means of control to protect consumers. However, the levels of detection of biological hazards during meat inspection have not been established in quantitative terms yet. Pork is the most frequently consumed meat in Europe. The aim of this study was to provide elements for quantifying levels of risk for pork consumers and lack of detection by meat inspection. Information concerning hazard identification and characterisation was obtained by the compilation and statistical analysis of data from 440 literature references. The incidence and severity of human cases due to pork consumption in Europe were assessed in order to calculate risk scores. A ratio of non-control was calculated for each biological hazard identified as currently established in Europe, i.e. the incidence of human cases divided by the prevalence of hazards on pork. Salmonella enterica, Yersinia enterocolitica and Campylobacter spp. were characterised by high incidence rates. Listeria monocytogenes, Clostridium botulinum and Mycobacterium spp. showed the highest severity scores. The three main high risk hazards involved in foodborne infections, Y. enterocolitica, S. enterica and Campylobacter spp. are characterised by high non-control ratios and cannot be detected by macroscopic examination of carcasses. New means of hazard control are needed to complement the classical macroscopic examination.
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PMID:Foodborne zoonoses due to meat: a quantitative approach for a comparative risk assessment applied to pig slaughtering in Europe. 1807 88

Discovering virulence factors of pathogenic bacteria is a key in understanding pathogenesis and for identification of targets for novel drugs and design of new vaccines. Comparative genomics, transcriptomics, and proteomics have become the popular tools in discovering the virulence factors in bacterial pathogens, such as Neisseria meningitidis, Yersinia pestis, Mycobacterium tuberculosis, and Staphylococcus aureus. In addition, proteomics has been employed successfully in the study of the mechanism of post-translationally modified proteins of bacterial pathogens. Once the putative virulence factors are identified by genomics and/or proteomics, their functions and mechanisms can be further investigated by phenotypic analyses including mutagenesis and biochemical methods and/or structural biology. Combination of these techniques will accelerate the developments of therapeutic drugs and vaccines in combating bacterial diseases.
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PMID:Discovery of virulence factors of pathogenic bacteria. 1828 25


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