Current drug targets. Infectious disorders最新文献_第10页

A review of macrolide treatment of atherosclerosis and abdominal aortic aneurysms. 大环内酯类药物治疗动脉粥样硬化和腹主动脉瘤的研究进展。

Current drug targets. Infectious disorders Pub Date : 2003-03-01 DOI: 10.2174/1568005033341984

Jes S Lindholt, Jette Stovring, Paul Lehm Andersen, Eskild W Henneberg, Lars Østergaard

{"title":"A review of macrolide treatment of atherosclerosis and abdominal aortic aneurysms.","authors":"Jes S Lindholt, Jette Stovring, Paul Lehm Andersen, Eskild W Henneberg, Lars Østergaard","doi":"10.2174/1568005033341984","DOIUrl":"https://doi.org/10.2174/1568005033341984","url":null,"abstract":"Seroepidemiological studies have shown an association between Chlamydia pneumoniae and atherosclerosis, the risk of acute myocardial infarction and abdominal aortic aneurysms (AAA). Several studies have detected C. pneumoniae in atherosclerotic lesions from coronary and carotid arteries, in AAA, and in sclerotic aortic valves. However, culturing of C. pneumoniae is difficult and has seldomly succeeded from atherosclerotic lesions. Thus, the pathogenicity is unknown, and the significance of detecting the organism is unresolved. Nevertheless, in a large observational study comparing the risk of cardiovascular events among recipients of macrolide versus pencillins, macrolide treatment reduced the risk of such events after relevant adjustment. Furthermore, in two out of three minor randomized clinical trials were patients with ischaemic heart disease were randomized into antibiotic treated and placebo groups, a significant reduction in serious end-points were noticed in patients receiving macrolide. Similarly, two other minor randomized trials showed that macrolide treatment inhibited growth of small AAA. Macrolide therapy thus seems potential to improve the outcome of severe ischaemic heart disease, and growth of AAA. If true, it not known whether this is transient because of macrolide's non-specific anti-inflammatory effect or latent infection, or permanent because of eradicating C. pneumoniae organisms. In order to clarify this, large and long term randomized trials are needed, as well as diagnostic methods that can differentiate between individuals who are or are not infected with C. pneumoniae. The latter are needed in order to clarify the impact of the presence of C. pneumoniae and to avoid overconsumption of antimicrobials, which can result in serious ecological problems.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"3 1","pages":"55-63"},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005033341984","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22230668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

Novel intervention strategies for Helicobacter pylori treatment. 幽门螺杆菌治疗的新干预策略。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342209

Brian Noonan, Richard A Alm

引用次数: 5

Genomic pathways to antifungal discovery. 抗真菌发现的基因组途径。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342344

Brian C Monk, Richard D Cannon

{"title":"Genomic pathways to antifungal discovery.","authors":"Brian C Monk, Richard D Cannon","doi":"10.2174/1568005023342344","DOIUrl":"https://doi.org/10.2174/1568005023342344","url":null,"abstract":"The limitations of the therapeutic antifungals are becoming increasingly apparent in the clinic due to their modest efficacy against life-threatening systemic fungal infections. These antifungals belong to only a few structural classes that affect a small range of targets, some are quite toxic in humans while the use of others, particularly the azole drugs, has encouraged the emergence of resistant clinical isolates and the selection of innately resistant fungal pathogens. Only a few new drugs based on novel targets are in clinical development, and these may be insufficient to overcome the changing tide of fungal disease. In parallel with the successful completion of the Saccharomyces cerevisiae and human genome sequencing projects, an increasing number of genome sequencing projects are being initiated and completed for significant fungal pathogens. The growing repository of genomic information, which is complemented by decades of genetic and biochemical study, is now available for genome-wide analysis of gene function and for incisive inter-genomic comparison, with the S. cerevisiae and human genomes providing key points of reference. Functional genomic and comparative genomic techniques, many of which were developed with S. cerevisiae, are being applied to fungal pathogens with the aim of obtaining an integrated view of fungal biology and to extract targets suitable for drug discovery. This review describes some of these techniques, their limitations and their increasing contribution to the antifungal discovery process through effective gene annotation, target identification and prioritization, and in the optimization of antifungal leads.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 4","pages":"309-29"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Assisting functional assignment for hypothetical Heamophilus influenzae gene products through structural genomics. 通过结构基因组学协助假设的流感嗜血杆菌基因产物的功能分配。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342281

Gary L Gilliland, Alexey Teplyakov, Galina Obmolova, Maria Tordova, Narmada Thanki, Jane Ladner, Osnat Herzberg, Kap Lim, Hong Zhang, Kui Huang, Zhong Li, Aleksandra Tempczyk, Wojiech Krajewski, Lisa Parsons, Deok Cheon Yeh, John Orban, Andrew J Howard, Edward Eisenstein, James F Parsons, Nicklas Bonander, Kathryn E Fisher, John Toedt, Prasad Reddy, C V Rao, Eugene Melamud, John Moult

{"title":"Assisting functional assignment for hypothetical Heamophilus influenzae gene products through structural genomics.","authors":"Gary L Gilliland, Alexey Teplyakov, Galina Obmolova, Maria Tordova, Narmada Thanki, Jane Ladner, Osnat Herzberg, Kap Lim, Hong Zhang, Kui Huang, Zhong Li, Aleksandra Tempczyk, Wojiech Krajewski, Lisa Parsons, Deok Cheon Yeh, John Orban, Andrew J Howard, Edward Eisenstein, James F Parsons, Nicklas Bonander, Kathryn E Fisher, John Toedt, Prasad Reddy, C V Rao, Eugene Melamud, John Moult","doi":"10.2174/1568005023342281","DOIUrl":"https://doi.org/10.2174/1568005023342281","url":null,"abstract":"The three-dimensional structures of Haemophilus influenzae proteins whose biological functions are unknown are being determined as part of a structural genomics project to ask whether structural information can assist in assigning the functions of proteins. The structures of the hypothetical proteins are being used to guide further studies and narrow the field of such studies for ultimately determining protein function. An outline of the structural genomics methodological approach is provided along with summaries of a number of completed and in progress crystallographic and NMR structure determinations. With more than twenty-five structures determined at this point and with many more in various stages of completion, the results are encouraging in that some level of functional understanding can be deduced from experimentally solved structures. In addition to aiding in functional assignment, this effort is identifying a number of possible new targets for drug development.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 4","pages":"339-53"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9

Natural and acquired macrolide resistance in mycobacteria. 分枝杆菌的天然和获得性大环内酯耐药。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342263

F Doucet-Populaire, K Buriánková, J Weiser, J-L Pernodet

{"title":"Natural and acquired macrolide resistance in mycobacteria.","authors":"F Doucet-Populaire, K Buriánková, J Weiser, J-L Pernodet","doi":"10.2174/1568005023342263","DOIUrl":"https://doi.org/10.2174/1568005023342263","url":null,"abstract":"The genus Mycobacterium contains two of the most important human pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, the etiologic agents of tuberculosis and leprosy, respectively. Other mycobacteria are mostly saprophytic organisms, living in soil and water, but some of them can cause opportunistic infections. The increasing incidence of tuberculosis as well as infections with non-tuberculous mycobacteria (NTM) in AIDS patients has renewed interest in molecular mechanisms of drug resistance in these pathogens. Mycobacteria show a high degree of intrinsic resistance to most common antibiotics. For instance, species from the M. tuberculosis complex (MTC) are intrinsically resistant to macrolides. Nevertheless, some semi-synthetic macrolides as the erythromycin derivatives clarithromycin, azithromycin and most recently the ketolides, are active against NTM, particularly Mycobacterium avium, and some of them are widely used for infection treatment. However, shortly after the introduction of these new drugs, resistant strains appeared due to mutations in the macrolide target, the ribosome. The mycobacterial cell wall with its specific composition and structure is considered to be a major factor in promoting the natural resistance of mycobacteria to various antibiotics. However, to explain the difference in macrolide sensitivity between the MTC and NTM, the synergistic contribution of a specific resistance mechanism might be required, in addition to possible differences in cell wall permeability. This mini-review summarizes the current knowledge on the natural and acquired macrolide resistance in mycobacteria, gives an overview of potential mechanisms implicated in the intrinsic resistance and brings recent data concerning a macrolide resistance determinant in the MTC.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 4","pages":"355-70"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1568005023342263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 49

Novel antibacterials: a genomics approach to drug discovery. 新型抗菌剂:药物发现的基因组学方法。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342227

Pan F Chan, Ricardo Macarron, David J Payne, Magdalena Zalacain, David J Holmes

{"title":"Novel antibacterials: a genomics approach to drug discovery.","authors":"Pan F Chan, Ricardo Macarron, David J Payne, Magdalena Zalacain, David J Holmes","doi":"10.2174/1568005023342227","DOIUrl":"https://doi.org/10.2174/1568005023342227","url":null,"abstract":"The appearance of antibiotic resistant pathogens, including vancomycin resistant Staphylococcus aureus, in the clinic has necessitated the development of new antibiotics. The golden age of antibiotic discovery, in which potent selective compounds were readily extracted from natural product extracts is over and novel approaches need to be implemented to cover the therapeutic shortfall. The generation of huge quantities of bacterial sequence data has allowed the identification of all the possible targets for therapeutic intervention and allowed the development of screens to identify inhibitors. Here, we described a number of target classes in which genomics has contributed to its identification. As a result of analyzing sequence data, all of the tRNA synthetases and all of the two-component signal transduction systems were readily isolated; which would not have been easily identified if whole genome sequences were not available. Fatty acid biosynthesis is a known antibacterial target, but genomics showed which genes in that pathway had the appropriate spectrum to be considered as therapeutic targets. Genes of unknown function may seem untractable targets, but if those that are broad spectrum and essential are identified, it becomes valuable to invest time and effort to determine their cellular role. In addition, we discuss the role of genomics in developing technologies that assist in the discovery of new antibiotics including microarray gridding technology. Genomics can also increase the chemical diversity against which the novel targets can be screened.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 4","pages":"291-308"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 39

Bioinformatics and the discovery of novel anti-microbial targets. 生物信息学与新型抗微生物靶点的发现。

Current drug targets. Infectious disorders Pub Date : 2002-12-01 DOI: 10.2174/1568005023342326

Craig Volker, James R Brown

{"title":"Bioinformatics and the discovery of novel anti-microbial targets.","authors":"Craig Volker, James R Brown","doi":"10.2174/1568005023342326","DOIUrl":"https://doi.org/10.2174/1568005023342326","url":null,"abstract":"Genomic research is playing a critical role in the discovery of new anti-microbial drugs. The rapid increase in bacterial and eukaryotic genome sequences allows for new and innovative ways for obtaining antimicrobial protein targets. Here, we describe a two level strategy for target identification and validation using computers (in silico). First, large scale comparative analyses of genome sequences were used to identify highly conserved genes which might be essential for in vitro and/or in vivo survival of bacterial pathogens. Lab-based experiments provided confirmation or validation of the hypothesis of in silico essentiality for over 350 individual genes. Over 200 validated, broad spectrum; yet highly specific gene targets, were identified in community infection pathogens. The second part of the target discovery strategy is an in-depth evolutionary, structural and cellular analysis of key drug targets. As an example, phylogenetic and structural analyses suggest that sequence and binding-pocket conservation in FabH (beta-ketoacyl-ACP synthase III) would allow for the development of small molecule inhibitors not only effective against a broad species spectrum of community bacterial pathogens but also as potential new therapies for tuberculosis and malaria.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 4","pages":"279-90"},"PeriodicalIF":0.0,"publicationDate":"2002-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22231864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 20

Pandemic of atopic diseases--a lack of microbial exposure in early infancy? 特应性疾病大流行——婴儿早期缺乏微生物接触?

Current drug targets. Infectious disorders Pub Date : 2002-09-01 DOI: 10.2174/1568005023342452

M Kalliomäki, E Isolauri

{"title":"Pandemic of atopic diseases--a lack of microbial exposure in early infancy?","authors":"M Kalliomäki, E Isolauri","doi":"10.2174/1568005023342452","DOIUrl":"https://doi.org/10.2174/1568005023342452","url":null,"abstract":"Improved hygienic conditions in Western societies have reduced early microbial exposure, which has been proposed as a reason for the continuously rising prevalence of atopy and subsequent atopic diseases: atopic eczema, allergic rhinitis and asthma (The Hygiene Hypothesis of Allergy). This hypothesis is supported by immunological data showing that the immune response to microbial antigens, both pathogenic and non-pathogenic ones, is accompanied by preferential expression of cytokines that counterbalance the T-helper 2-polarized cytokine production of neonates, the continuity of which might lead to enhanced IgE production, atopy, and atopic disease. Experimental, epidemiological and clinical studies, conducted over the last decade, indicate that non-pathogenic microbes in the gut might be a major factor essential for the maturation of the human immune system to a nonatopic mode. A recent randomised, placebo-controlled trial demonstrated that perinatal administration of probiotics, cultures of potentially beneficial bacteria of the healthy gut microflora, halved the later development of atopic eczema during the first two years of life. Some putative mechanisms of action of gut commensals in host-microbe interactions have been described. Two structural components of bacteria, the lipopolysaccharide portion of Gram-negative bacteria and specified CpG motif in bacterial DNA, activate immunomodulatory genes via Toll-like receptors present e.g. on intestinal epithelial cells thus controlling physiological cytokine milieu in the gut. Probiotics have also been shown to reverse increased intestinal permeability and to reduce antigen load in the gut by degrading and modifying macromolecules. The actual preventive role of natural and genetically constructed supplementary microbes in the development of immunological diseases, like allergy, remains to be elucidated.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 3","pages":"193-9"},"PeriodicalIF":0.0,"publicationDate":"2002-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22137987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 54

Histidine kinase-mediated signal transduction systems of pathogenic microorganisms as targets for therapeutic intervention. 组氨酸激酶介导的病原微生物信号转导系统作为治疗干预的靶点。

Current drug targets. Infectious disorders Pub Date : 2002-09-01 DOI: 10.2174/1568005023342443

K Stephenson, J A Hoch

{"title":"Histidine kinase-mediated signal transduction systems of pathogenic microorganisms as targets for therapeutic intervention.","authors":"K Stephenson, J A Hoch","doi":"10.2174/1568005023342443","DOIUrl":"https://doi.org/10.2174/1568005023342443","url":null,"abstract":"Pathogenic bacteria must be able to sense and respond rapidly to signals emanating from the host environment and use the signals to modulate the expression of genes required for the infection process. Two-component signal transduction systems, and their more complex variants known as phosphorelays, are woven within the fabric of bacterial cellular regulatory processes and are used to regulate the expression of genes involved in the virulence and antibiotic resistance responses of a large number of pathogens of major public health concern. The emergence of strains of pathogenic bacteria that are resistant to multiple antibiotics has driven the search for new targets and/or modes of action for anti-microbial agents. The presence of essential two-component systems in bacteria and the central role that these regulatory systems play in virulence and antibiotic resistance has meant that two-component systems and phosphorelays have been recognized as targets for antimicrobial intervention. This review will discuss the role of these signal transduction pathways in virulence responses and antibiotic sensitivity of pathogenic microorganisms and their potential use as targets for antimicrobial therapy. In addition, the current status on the development of inhibitors specific for two-component systems will be discussed.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 3","pages":"235-46"},"PeriodicalIF":0.0,"publicationDate":"2002-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22137990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 26

The role of the cytoskeleton in the life cycle of viruses and intracellular bacteria: tracks, motors, and polymerization machines. 细胞骨架在病毒和细胞内细菌生命周期中的作用：轨道、马达和聚合机。

Current drug targets. Infectious disorders Pub Date : 2002-09-01 DOI: 10.2174/1568005023342407

E L Bearer, P Satpute-Krishnan

{"title":"The role of the cytoskeleton in the life cycle of viruses and intracellular bacteria: tracks, motors, and polymerization machines.","authors":"E L Bearer, P Satpute-Krishnan","doi":"10.2174/1568005023342407","DOIUrl":"10.2174/1568005023342407","url":null,"abstract":"Recent advances in microbiology implicate the cytoskeleton in the life cycle of some pathogens, such as intracellular bacteria, Rickettsia and viruses. The cellular cytoskeleton provides the basis for intracellular movements such as those that transport the pathogen to and from the cell surface to the nuclear region, or those that produce cortical protrusions that project the pathogen outwards from the cell surface towards an adjacent cell. Transport in both directions within the neuron is required for pathogens such as the herpesviruses to travel to and from the nucleus and perinuclear region where replication takes place. This trafficking is likely to depend on cellular motors moving on a combination of microtubule and actin filament tracks. Recently, Bearer et al. reconstituted retrograde transport of herpes simplex virus (HSV) in the giant axon of the squid. These studies identified the tegument proteins as the viral proteins most likely to recruit retrograde motors for the transport of HSV to the neuronal nucleus. Similar microtubule-based intracellular movements are part of the biological behavior of vaccinia, a poxvirus, and of adenovirus. Pathogen-induced surface projections and motility within the cortical cytoplasm also play a role in the life cycle of intracellular pathogens. Such motility is driven by pathogen-mediated actin polymerization. Virulence depends on this actin-based motility, since virulence is reduced in Listeria ActA mutants that lack the ability to recruit Arp2/3 and polymerize actin and in vaccinia virus mutants that cannot stimulate actin polymerization. Inhibition of intracellular movements provides a potential strategy to limit pathogenicity. The host cell motors and tracks, as well as the pathogen factors that interact with them, are potential targets for novel antimicrobial therapy.","PeriodicalId":84525,"journal":{"name":"Current drug targets. Infectious disorders","volume":"2 3","pages":"247-64"},"PeriodicalIF":0.0,"publicationDate":"2002-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616324/pdf/nihms-242012.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22137992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0