天然植物抗假丝酵母菌活性成分的研究

临床真菌感染的发病率和死亡率逐年上升,其中以假丝酵母菌为代表的侵袭性真菌感染尤为严重,目前主要抗真菌药物的耐药性日趋严重,且多数具有毒副作用,寻找安全有效的新型抗真菌药物迫在眉睫。天然植物中抗真菌活性成分来源广泛,具有低毒、广谱、作用途径多样化等优点,成为新型抗真菌药物的一个重要研究方向。本文主要综述了近年来从天然植物中筛选抗假丝酵母菌活性成分的研究。     

抗真菌药物的联合应用

目前真菌感染,特别是免疫缺陷患者中侵入性真菌感染的发病率和死亡率在不断增加,但现有抗真菌药物可选择范围小、毒副作用大而且耐药情况日渐严重。联合用药这一概念的提出,给耐药株及严重性真菌感染提供了新的治疗途径,并且已在临床中广泛运用。该文对不同种类抗真菌药物联用的研究成果及作用机制做一综述。     

天然药物中抗HIV活性成分研究进展

天然产物往往具有独特的化学结构,是发现新药或药物先导物的重要途径之一.目前,从天然药物中发现了多种结构类型的具有抗HIV活性的化合物,如多糖类、生物碱类、香豆素类、黄酮类、木脂素类、醌类、酚酸类、萜类等,并且其作用机制并不局限于抑制逆转录酶或蛋白酶,可在HIV复制周期的各个环节发挥作用,本文按天然产物的结构类型进行归纳,综述了近年来源自天然药物的抗HIV活性成分研究进展,总结了的151个具有抗HIV活性的天然产物结构及其活性测试数据,以期为从天然化学成分中寻找、发现并研究开发有效的抗艾滋病药物提供线索.     

Ridaforolimus体外单独或联合氟康唑抗念珠菌作用的研究

由念珠菌感染引起的侵袭性念珠菌病治疗困难、死亡率高,是临床一大难题。氟康唑是目前治疗该病的一线用药,但近年来耐药菌株逐渐增多,治疗困难。因此,开发新的有效抗真菌药物或发现可提高现有抗真菌药物活性的化合物十分必要。通过体外抗真菌药物敏感性试验,我们发现TOR通路抑制剂ridaforolimus具有抗念珠菌作用。随后我们通过纸片法及微量液基稀释法评价该化合物单独或与氟康唑联合对念珠菌的抗菌效果。结果表明ridaforolimus对念珠菌有杀伤作用,在与氟康唑联合时增强了氟康唑的抗念珠菌能力,逆转了白念珠菌对氟康唑的耐药,并将氟康唑由抑菌剂转化为杀菌剂。本研究为ridaforolimus作为新型抗真菌药及氟康唑增敏剂提供了一定理论基础。     

抗真菌药物及其耐药机制研究进展

侵袭性真菌感染,由于其高发病率和死亡率,对人类健康造成严重威胁。针对侵袭性真菌自身生长繁殖的生物学过程,人们开发了不同的抗真菌药物对其进行阻断、干扰,从而达到杀菌抑菌的目的。我们简要介绍临床常见抗真菌药物的种类、作用机制、耐药机制以及应对耐药的方法。     

羊毛硫肽类化合物(Lanthipeptide)生物合成新进展

羊毛硫肽化合物(Lanthipeptides)是由核糖体合成并经过翻译后修饰得到的一大类肽类天然产物。这类化合物广泛的产生于不同种类的细菌,具有丰富的结构和生物活性多样性,为活性药物研究和开发提供重要的来源。本文综述了近几年来羊毛硫肽化合物生物合成进展,从其合成酶结构,进化机制,区域和立体选择性控制等方面进行了简要的讨论,展示了羊毛硫肽类化合物生物合成中特殊而迷人的酶学机制。     

化学基因组学在抗真菌药物研究中的应用CSCD

真菌感染特别是侵袭性感染严重威胁人类健康,而我们应对真菌感染的药物种类却很少。基于细胞表型变化的抗真菌药物筛选,容易获得活性先导物,但后续对其作用靶点和作用机制的研究通常需要耗费更多的时间和精力,这已成为抗真菌药物研发的瓶颈。识别活性化合物的分子靶点,对于进一步优化改造先导物获得高效低毒的候选药物至关重要。化学基因组学能在活细胞基因组水平上发现先导物的作用靶点,利用该策略,近年来已有多个抗真菌先导物发现了作用靶点。该文主要介绍了化学基因组学的技术特点,以及近年来在发现抗真菌先导物作用靶点方面的应用。     

微生物中抗耐药菌活性天然产物的研究进展

近年来,细菌耐药性已成为全球性问题。微生物作为抗生素的重要来源,在发掘抗耐药菌新型抗生素的研究中承担了重要角色,许多微生物来源天然化合物展现了显著的抗耐药菌活性。本文主要综述了近十年发现的微生物源抗耐药菌天然化合物,并概括了抗耐药菌活性天然产物的筛选方法,以期对抗耐药菌新型抗生素的发现做铺垫。     

黑素与真菌抗药性的研究进展

黑素是生物界普遍存在的一类暗褐色或黑色物质,在真菌主要存在于细胞壁,与真菌的形态和毒力密切相关,具有增强真菌在逆环境中的存活力、抵抗宿主免疫攻击和耐受抗真菌药物等作用。随着临床真菌感染发病率逐渐上升,对抗真菌药物耐药现象增多,探讨真菌黑素与其抗药性关系将为阐明真菌感染的发病机制奠定基础,为开发新型的抗真菌药物提供依据。本文重点从真菌黑素的生物学特性及其与人类致病真菌抗药性方面研究进展进行阐述。     

三唑类抗真菌新药泊沙康唑和伏立康唑简介

随着侵袭性真菌感染的发病率和死亡率逐年增多,新近问世的新型抗真菌药物也越来越多。新一代广谱三唑类抗真菌药物泊沙康唑和伏立康唑,在体内和体外均有较强的抗真菌活性,临床上用其来预防和治疗侵袭性真菌感染。两药具有共有的作用机制,在抗真菌活性、药物代谢及安全性方面有着各自特点。分子结构上泊沙康唑和伏立康唑优于原有药物伊曲康唑和氟康唑,从而具备更强、更广的抗菌谱。两药的研发和应用表明抗真菌药物研究正朝着高效、广谱、低毒的方向发展,成为治疗各种类型真菌感染新的有力手段。然而,两药在临床研究和血药浓度监测方面仍待深入探究。本文将从分子结构、作用机制、适应症和药代动力学方面介绍两药,并对两药在未来的临床应用进行展望,为临床应用提供帮助。     

Antifungals discovery: an insight into new strategies to combat antifungal resistance

Undeniably, new antifungal treatments are necessary against pathogenic fungi. Fungal infections have significantly increased in recent decades, being highlighted as important causes of morbidity and mortality, particularly in immunocompromised patients. Five main antifungal classes are used: (i) azoles, (ii) echinocandins, (iii) polyenes, (iv) allylamines and (v) pyrimidine analogues. Moreover, the treatment of mycoses has several limitations, such as undesirable side effects, narrow activity spectrum, a small number of targets and fungal resistance, which are still of major concern in clinical practice. The discovery of new antifungals is mostly achieved by the screening of natural or synthetic/semisynthetic chemical compounds. The most recent discoveries in drug resistance mechanism and their avoidance were explored in a review, focusing on different antifungal targets, as well as new agents or strategies, such as combination therapy, that could improve antifungal therapy.

Significance and Impact of the Study

The failure to respond to antifungal therapy is complex and is associated with microbiological resistance and increased expression of virulence in fungal pathogens. Thus, this review offers an overview of current challenges in the treatment of fungal infections associated with increased antifungal drug resistance and the formation of biofilms in these opportunistic pathogens. Furthermore, the most recent and potential strategies to combat fungal pathogens are explored here, focusing on new agents as well as innovative approaches, such as combination therapy between antifungal drugs or with natural compounds.     

Promising antifungal agents: A minireview

In the recent past, prevalence of life threatening fungal diseases have increased rapidly in immune-compromised cases such as acquired immunodeficiency syndrome (AIDS), cancer, organ transplant etc. Side by side, the appearance of drug resistance to the presently available antifungal therapeutics is on a rapid rise. It has become a top priority for the academia and pharmaceutical industries to develop new antifungal agents able to combat this resistance, and at the same time, possess potential broad spectrum of activity and minimum toxicity. An understanding of the pharmacological interactions between antifungal agents and their targets offers opportunities for design of new therapeutics. This review discusses the various methodology of drug design, structure activity relationships (SARs), and mode of action of variety of new antifungal agents.     

Pathogenicity and drug resistance in Candida albicans and other yeast species. A review

Pathogenic yeasts from the genus Candida can cause serious infection in humans particularly, in immunocompromised patients and are now recognized as major agents of hospital acquired (nosocomial) infections. In the recent years, there has been a marked increase in the incidence of treatment failures in candidiasis patients receiving long-term antifungal therapy, which has posed a serious problem in its successful use in chemotherapy. Candida cells acquire drug resistance (MDR) during the course of the treatment. The mechanisms of resistance to azole antifungal agents have been elucidated in Candida species and can be mainly categorized as (i) changes in the cell wall or plasma membrane, which lead to impaired drug (azole) uptake; (ii) alterations in the affinity of the drug target Erg11p (lanosterol 14alpha-demethylase) especially to azoles or in the cellular content of Erg11p due to target site mutation or overexpression of the ERG11 gene; and (iii) the efflux of drugs mediated by membrane transport proteins belonging to the ATP-binding cassette (ABC) transporters, namely CDR1 and CDR2 or to the major facilitator superfamily (MFS) transporter, CaMDR1. Many such manifestations are associated with the formation of Candida biofilms including those occurring on devices like indwelling intravascular catheters. Biofilm-associated Candida show uniform resistance to a wide spectrum of antifungal drugs. A combination of different resistance mechanisms is responsible for drug resistance in clinical isolates of Candida species.     

Resistance of human fungal pathogens to antifungal drugs

Resistance mechanisms can be engaged in clinically relevant fungal pathogens under different conditions when exposed to antifungal drugs. Over past years, active research was undertaken in the understanding of the molecular basis of antifungal drug resistance in these pathogens, and especially against the class of azole antifungals. The isolation of various alleles of the gene encoding the target of azoles has enabled correlation of the appearance of resistance with distinct mutations. Resistance mechanisms to azoles also converge to the upregulation of multidrug transporter genes, whose products have the capacity to extrude from cells several chemically unrelated antifungal agents and toxic compounds. Genome-wide studies of azole-resistant isolates are now permitting a more comprehensive analysis of the impact of resistance on gene expression, and may deliver new clues to their mechanisms. Several laboratories are also exploring, as well as possible alternative resistance pathways, the role of biofilm formation by several fungal species in the development of resistance to various antifungals, including azoles.     

抗真菌药物增效剂的研究进展

近年来,真菌耐药发生率呈逐年上升趋势,真菌对氟康唑等氮唑类药物的耐药性最为严重,成为临床抗真菌治疗失败的原因之一.对于耐药真菌的治疗,往往采用加大剂量或联合用药的方法.此外,文献报道了一些植物提取物、小分子化合物能显著增强抗真菌药物对耐药真菌的敏感性,两个药物的协同作用有望成为治疗耐药真菌的新策略.该文结合近几年的研究报道,简要综述了抗真菌药物增效剂的研究进展.     

The biology and chemistry of antifungal agents: A review

In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed.     

Invasive Aspergillosis: Resistance to Antifungal Drugs

Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis remains unacceptably high. Resistance of the Aspergillus spp. species to antifungal drugs increased in the last 20 years with the increase in antifungal drugs use and might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, have brought resistance testing to the forefront of clinical mycology. Recent modifications in taxonomy and understanding of the acquired resistance mechanisms of Aspergilli to drugs should support a better management of Aspergillus infections. In this paper, we review the current knowledge on epidemiology and underlying mechanisms involved in antifungal resistance in Aspergillus.     

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

Pharmaceutically active secondary metabolites of microorganisms

The antibiotics have been useful in our battles against infectious bacteria and fungi for over 50 years. However, many antibiotics are used commercially, or are potentially useful, in medicine for activities other than their antibiotic action. They are used as antitumor agents, immunosuppressive agents, hypocholesterolemic agents, enzyme inhibitors, antimigraine agents, and antiparasitic agents. A number of these products were first discovered as antibiotics which failed in their development as such, or as mycotoxins. In addition to the above alternative applications, new powerful antibiotics have been discovered and commercialized in recent years and others are in clinical testing at the moment. A few successful secondary metabolites appear to have no antibiotic activity. The recently increased development of resistance to older antibacterial and antifungal drugs is being met with the use or clinical testing of older, underutilized or previously nondeveloped narrow-spectrum antibacterial products as well as powerful semisynthetic antifungal agents. Received: 28 December 1998 / Received revision: 26 April 1999 / Accepted: 1 May 1999     

白念珠菌耐药机制新进展

近年来对于深部真菌感染的研究报道越来越多,其已日益成为一些重要疾病临床治疗过程中的常见并发症,其中,白念珠菌病的发病率仍居高不下.虽然目前有多种抗真菌药物应用于临床,但其耐药现象愈来愈严重,给临床治疗带来了极大的挑战.近来有关白念珠菌耐药机制的研究有了较新的进展.该文就新发现的白念珠菌的耐药机制,作一概述.