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随着真菌病发病率的不断上升,抗真菌药物使用频率和剂量增加,致病真菌的耐药问题逐渐突出。合成开发新一代结构的抗真菌药是目前药物研究的热点,但如何提高现有抗真菌药物的抗菌作用,也是抗真菌研究的另一个热点领域。现结合国内外最新文献,全面阐述抗真菌增效剂的研究成果,展示目前抗真菌研究的新思路。 相似文献
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近30年来,侵袭性真菌感染发病率持续上升,病死率居高不下,而治疗药物十分有限是造成其高致死率的重要因素之一。因此,发现新的抗真菌靶点和药物,已成为迫切需要。正在研究的新的抗真菌靶点如下:一是信号通路介导的抗真菌靶点,包括钙调神经磷酸酶及其分子伴侣Hsp90、3-磷酸肌醇依赖性蛋白激酶(PKH)以及参与Ras蛋白修饰的相关酶等,其拮抗剂包括传统免疫抑制剂的类似物以及Hsp90抗体、KP-372-1和PS77以及手霉素A等;二是GPI锚定蛋白合成通路的催化酶,其抑制剂有E1210和M720等化合物;三是分泌型天冬氨酸蛋白酶,肽类、逆转录病毒抑制剂,以及砜类的衍生物等均可以抑制这一靶点;四是海藻糖的合成的两个关键酶Tps1和Tps2。鉴于侵袭性真菌感染严重影响人类公共健康安全,而新型抗真菌药物的研发又依赖于新靶点的探索,因此,本文靶向这一核心真菌临床问题,系统介绍了当前新的抗真菌药物靶点发展概况,并在靶点选择可行性以及针对靶点的药物研发策略上提出见解。 相似文献
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真菌鞘脂代谢及其与抗真菌药物关系研究进展 总被引:1,自引:0,他引:1
鞘脂是真核细胞中普遍存在的成分,它在真核细胞的胞吞、胞饮、信号转导、细胞的生长、凋亡、分化、衰老等过程中起着非常重要的作用.该文论述了真菌鞘脂代谢的途径及参与其合成的相关酶和基因,并比较了真菌与哺乳动物鞘脂代谢途径的不同,旨在为研究新型无公害抗真菌药物提供理论依据. 相似文献
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细胞壁是细菌区别真核生物的一个重要特征,因此其合成途径早已成为人们广泛研究的抗菌药物靶标来源.目前临床上上广泛应用的抗生素,如β内酰胺类(青霉素、头孢菌素类等)和糖肽类(万古霉素等)抗生素主要就是通过阻断细菌的细胞壁合成而起到杀菌作用[1]. 相似文献
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A comparative study among amphotericin B, 5-fluorocytosine, itraconazole and fluconazole in the treatment of experimental cryptococcosis in mice, was carried out.Seventy male Balb C mice were inoculated intraperitoneally with 107 cells of Cryptococcus neoformans var. neoformans. They were divided in 7 groups of 10 animals each one: 1) treated with fluconazole by gavage at a daily dose of 16 mg/kg; 2) treated with itraconazole by gavage at a daily dose of 16 mg/kg; 3) treated with 5-fluorocytosine by gavage at a daily dose of 300 mg/kg; 4) treated with amphotericin B intraperitoneally at a dose of 6 mg/kg every other day; 5) control animals receiving polietilenglicol 200 by gavage; 6) control animals receiving distilled water by gavage and 7) control animals receiving sterile distilled water by intraperitoneal route. All the treatments started 5 days after the challenge inoculation and they were given for 2 weeks.The following parameters were taken into account: survival time, macroscopic aspect of the organ after the complete autopsy, microscopic investigation of yeasts in brain, lungs, spleen and liver, histopathology studies of these organs, the colony forming units per gram and massive seeding of brain and lungs.The survival index of the different groups was the most efficient method to measure the antifungal compounds activity. Amphotericin B increased significantly the animals survival and modified the histopathologic response in the studied organs. The colony forming units and the massive seeding in brain and lung showed that this antifungal agent is unable of producing the biological cure of this experimental model.The remaining drugs assayed did not promote important modifications in the histopathologic picture as well as in the tissues cultures. However, the three drugs increased the animals survival. In this aspect, fluconazole proved to be slightly superior. 相似文献
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随着免疫功能缺陷人群的增多,侵袭性真菌感染(invasive fungal infections,IFIs)的发病率和死亡率逐年上升,严重威胁人类健康。目前临床常用抗侵袭性真菌感染药物有三唑类(氟康唑)、多烯类(两性霉素B)、棘白菌素类(卡泊芬净)等,然而这些药物并不能满足临床需要,侵袭性真菌感染的死亡率仍居高不下。因此,本文着重于目前处于临床研究阶段的抗真菌感染新药,根据作用靶点不同依次介绍:作用于细胞壁的新型葡聚糖合成酶抑制剂CD101和SCY-078、几丁质合成酶抑制剂尼可霉素Z、GPI锚定蛋白抑制剂APX001;作用于细胞膜的CYP51抑制剂VT-1161和VT-1129、破坏细胞膜通透性药物CAmB;影响细胞代谢的嘧啶合成抑制剂F901318,以及生物制剂包括细胞表面凝集素样序列3蛋白疫苗(NDV-3)和抗真菌感染抗体Mycograb。本文主要综述了上述新药的研究进展,包括作用机制、体内外活性、临床研究结果等,为相关药物的研发与未来的临床应用提供参考。 相似文献
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外阴阴道念珠菌病(vulvovaginal candidiasis,VVC)是女性的常见病。本研究收集了2018年1月-12月苏州地区VVC患者分离的289株念珠菌进行了病原学鉴定和包括棘白菌素类、新三唑类药物在内的9种抗真菌药物体外敏感性分析。本文采用核糖体RNA的D1/D2基因进行念珠菌菌种鉴定。参照M27-A3方法检测其对9种抗真菌药物(包括棘白菌素类及新三唑类药物)的体外敏感性。结果表明,289株VVC念珠菌菌株中,白念珠菌259株、光滑念珠菌14株、克柔念珠菌10株、热带念珠菌4株、近平滑念珠菌2株。259株VVC白念珠菌对棘白菌素类体外敏感性好,对米卡芬净敏感性高于另外两种棘白菌素类;对两性霉素B、5-氟胞嘧啶、氟康唑敏感性好;但对伊曲康唑、伏立康唑敏感性差;对泊沙康唑敏感性好。光滑念珠菌株和克柔念珠菌分离株对卡泊芬净敏感性差,但对米卡芬净、阿尼芬净敏感性好;光滑念珠菌株对两性霉素B、5-氟胞嘧啶体外敏感性好,对伊曲康唑敏感性差,对泊沙康唑敏感性好;伏立康唑对光滑念珠菌分离株MIC50/90为0.5/1μg/mL;克柔念珠菌对伊曲康唑、伏立康唑50%耐药;4株热带念珠菌对伊曲康唑50%耐药,对卡泊芬净、氟康唑、伏立康唑100%耐药,对其余5种抗真菌药物敏感。近平滑念珠菌对9种抗真菌药物均敏感。白念珠菌仍为苏州地区VVC的主要病原菌,其次是光滑念珠菌和克柔念珠菌,它们对临床常用药物伊曲康唑、伏立康唑、卡泊芬净敏感性差。研究结果提示对VVC病人常规进行分泌物培养、菌种鉴定,对苏州地区临床医生制定VVC治疗方案具有重要参考价值。尽管棘白菌素类、两性霉素B、5-氟胞嘧啶、新三唑类药物尚未应用到VVC的临床治疗中,但是这些药物对VVC病原体总体敏感性较好,未来有望成为氟康唑、咪唑类药物治疗失败患者的新选择。 相似文献
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The Penicillium digitatum protein O‐mannosyltransferase Pmt2 is required for cell wall integrity,conidiogenesis, virulence and sensitivity to the antifungal peptide PAF26 下载免费PDF全文
Eleonora Harries Mónica Gandía Lourdes Carmona Jose F. Marcos 《Molecular Plant Pathology》2015,16(7):748-761
The activity of protein O‐mannosyltransferases (Pmts) affects the morphogenesis and virulence of fungal pathogens. Recently, PMT genes have been shown to determine the sensitivity of Saccharomyces cerevisiae to the antifungal peptide PAF26. This study reports the identification and characterization of the three Pdpmt genes in the citrus post‐harvest pathogen Penicillium digitatum. The Pdpmt genes are expressed during fungal growth and fruit infection, with the highest induction for Pdpmt2. Pdpmt2 complemented the growth defect of the S. cerevisiae Δpmt2 strain. The Pdpmt2 gene mutation in P. digitatum caused pleiotropic effects, including a reduction in fungal growth and virulence, whereas its constitutive expression had no phenotypic effect. The Pdpmt2 null mutants also showed a distinctive colourless phenotype with a strong reduction in the number of conidia, which was associated with severe alterations in the development of conidiophores. Additional effects of the Pdpmt2 mutation were hyphal morphological alterations, increased sensitivity to cell wall‐interfering compounds and a blockage of invasive growth. In contrast, the Pdpmt2 mutation increased tolerance to oxidative stress and to the antifungal activity of PAF26. These data confirm the role of protein O‐glycosylation in the PAF26‐mediated antifungal mechanism present in distantly related fungal species. Important to future crop protection strategies, this study demonstrates that a mutation rendering fungi more resistant to an antifungal peptide results in severe deleterious effects on fungal growth and virulence. 相似文献
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Previous mechanical studies using algae have concentrated on cell extension and growth using creep-type experiments, but
there appears to be no published study of their failure properties. The mechanical strength of single large internode cell
walls (up to 2 mm diameter and 100 mm in length) of the charophyte (giant alga) Chara corallina was determined by dissecting cells to give sheets of cell wall, which were then notched and fractured under tension. Tensile
tests, using a range of notch sizes, were conducted on cell walls of varying age and maturity to establish their notch sensitivity
and to investigate the propagation of cracks in plant cell walls. The thickness and stiffness of the walls increased with
age whereas their strength was little affected. The strength of unnotched walls was estimated as 47 ± 13 MPa, comparable to
that of some grasses but an order of magnitude higher than that published for model bacterial cellulose composite walls. The
strength was notch-sensitive and the critical stress intensity factor K
1c was estimated to be 0.63 ± 0.19 MNm−3/2, comparable to published values for grasses.
Received: 4 April 2000 / Accepted: 21 July 2000 相似文献
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Mutations of the secondary cell wall 总被引:6,自引:0,他引:6
It has not been possible to isolate a number of crucial enzymes involved in plant cell wall synthesis. Recent progress in identifying some of these steps has been overcome by the isolation of mutants defective in various aspects of cell wall synthesis and the use of these mutants to identify the corresponding genes. Secondary cell walls offer numerous advantages for genetic analysis of plant cell walls. It is possible to recover very severe mutants since the plants remain viable. In addition, although variation in secondary cell wall composition occurs between different species and between different cell types, the composition of the walls is relatively simple compared to primary cell walls. Despite these advantages, relatively few secondary cell wall mutations have been described to date. The only secondary cell wall mutations characterised to date, in which the basis of the abnormality is known, have defects in either the control of secondary cell wall deposition or secondary cell wall cellulose or lignin biosynthesis. These mutants have, however, provided essential information on secondary cell wall biosynthesis. 相似文献
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Vronique Ongenae Adam Sidi Mabrouk Marjolein Crooijmans Daniel Rozen Ariane Briegel Dennis Claessen 《Open biology》2022,12(6)
Phages are highly abundant in the environment and pose a major threat for bacteria. Therefore, bacteria have evolved sophisticated defence systems to withstand phage attacks. Here, we describe a previously unknown mechanism by which mono- and diderm bacteria survive infection with diverse lytic phages. Phage exposure leads to a rapid and near-complete conversion of walled cells to a cell-wall-deficient state, which remains viable in osmoprotective conditions and can revert to the walled state. While shedding the cell wall dramatically reduces the number of progeny phages produced by the host, it does not always preclude phage infection. Altogether, these results show that the formation of cell-wall-deficient cells prevents complete eradication of the bacterial population and suggest that cell wall deficiency may potentially limit the efficacy of phage therapy, especially in highly osmotic environments or when used together with antibiotics that target the cell wall. 相似文献
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植物激素在植物细胞壁扩展中的作用 总被引:3,自引:0,他引:3
细胞壁不仅是植物细胞结构的重要组成部分,而且控制着细胞的大小、形状和生长。细胞经有丝分裂后,原生质体吸水膨胀,细胞壁重塑,新生壁物质合成,纤维素定向沉积等引发细胞壁生长。在这些过程中,乙烯(ethylene,ET)、生长素(auxin)、赤霉素(gibberellin,GA)、油菜素甾醇(brassinosteroids,BR)等植物激素调控细胞壁生长相关酶类如纤维素合酶复合体(cellulose synthase A,CESA)、扩展素(expansin,EXP)、木葡聚糖内糖基转移酶/水解酶(xyloglucan endotran glucosylase/hydrolase,XET/XTH)的表达活性,进而调控细胞壁扩展,促使细胞壁的生长。 相似文献
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Abstract Wall mannoproteins from Kluyveromyces lactis have been solubilised by treatment of cell walls with sodium dodecyl sulphate (SDS) or zymolyase. While the former reagent liberates a large number of molecular species, zymolyase preferentially releases a high-molecular-weight material that is sensitive to endo- β - N -acetylglucosaminidase H, and a 29-kDa molecule that reacts with the antiserum raised against a similar species from walls of Saccharomyces cerevisiae . In contrast with observations on isolated walls of S. cerevisiae , dithiothreitol pretreatment of K. lactis walls does not enhance the effect of zymolyase upon mannoprotein release. However, the action of thiol agents is still necessary to obtain protoplasts by zymolyase digestion from K. lactis whole cells. 相似文献
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1557株酵母菌的鉴定及其药敏试验分析 总被引:9,自引:2,他引:9
目的 研究临床分离的酵母菌种类及其对药物的敏感性。方法 采用API 20C、显色培养基对2004-2005年北京协和医院细菌室分离到的1557株念珠菌进行菌株鉴定,并对2005年收集的酵母菌采用ATB FUNGUS 2对氟康唑,伊曲康唑,两性霉素B,5-氟胞嘧啶进行药物敏感性试验;并以whonet 5.3软件进行结果分析。结果 在1557株酵母菌中自念珠菌为57.5%,热带念珠菌为17.0%,光滑念珠菌为14.8%,克柔念珠菌为2.8%,近平滑念珠菌为2.3%,葡萄牙念珠菌为0.9%,新生隐球菌为0.7%,季也蒙念珠菌0.4%,其他菌株共为3.6%。药敏结果显示:近平滑念珠菌、白念珠菌、热带念珠菌、光滑念珠菌、克柔念珠菌和其他念珠菌对氟康唑的敏感率分别为100%、97.6%、94.5%、81.1%、9.1%和75.0%;对5-氟胞嘧啶的敏感率分别为100%、98.0%、98.0%、99.0%、9.5%和88.0%。伊曲康唑对克柔念珠菌和未鉴定到种的念珠菌的MIC90为1μg/ml,光滑念珠菌为4μg/ml,热带念珠菌为0.5μg/ml,白念珠菌和近平滑念珠菌均为0.125μg/ml;两性霉素B对所有念珠菌的MIC50和MIC90均为0.5μg/ml。结论 白念珠菌比例最高,其次为热带念珠菌及光滑念珠菌。5-氟胞嘧啶和氟康唑对除克柔念珠菌之外的所有念珠菌敏感度都很高,两性霉素B对所有念珠菌的MIC90都很低,伊曲康唑对除克柔念珠菌和光滑念珠菌之外的其他菌株的MIC90较低。 相似文献