氮杂内酯类抗生素研究现状

综述大环内酯类抗生素的发展及作用机制以及氮杂内酯类抗生素的结构修饰与构效关系研究进展。作为新一代半合成大环内酯类衍生物，氮杂内酯具有抗菌谱广、药物动力学性质优良等特点。     

酮内酯类抗生素的研究进展

几十年来大环内酯类抗生素在临床上的广泛应用取得了很好的疗效。但随着大环内酯类抗生素临床应用的增加 ,细菌对其耐药性也不断上升 ,促使人们加快对大环内酯类抗生素构效关系研究 ,从而开发更有效更具潜力的药物。近年来国外在对红霉素的构效关系的深入研究中 ,开发出了同时对耐药菌有效的酮内酯类药物 ,如泰利霉素 ,噻霉素。对酮内酯类药物的研究开发状况作一介绍     

酮内酯类抗生素的研究进展（上）

几十年来大环内酯类抗生素在临床上的广泛应用取得了很好的疗效，但随着大环内酯类抗生素临床应用的增加，细菌对其耐药性也不断上升，促使人们加快对大环内酯类抗生素构效关系研究，从而来开发更有效更具潜力的药物；近年来国外在对红霉素的构效关系的深入研究中，开发出了同时对耐药茵有效的酮内酯大环内酯类药物，如泰利霉素，噻霉素；本文简要对大环内酯酮内酯类药物的研究开发状况作一介绍一     

大环内酯类抗生素的发展与展望

简要介绍大环内酯类抗生素发展近况,讨论了大环内酯类抗生素的作用机制、耐药机制、构效关系及泰利霉素(Telithromycin)和ABT-773(Cethromycin,喹红霉素)的药理、临床性质。     

红霉素衍生物的成环修饰

半合成红霉素衍生物是临床上一类重要的抗感染药物,但细菌对现有品种产生日益严重的耐药性,因此急需研发出对耐药菌有效的新型大环内酯类抗生素。在深入研究抗菌作用机制的基础上,对红霉素的化学结构进行修饰与改造,特别是通过环状体系的引入与变换这一有效的药物设计方法,已获得了很多结构新颖且具有较强抗菌活性的红霉素衍生物。综述近年来在红霉素衍生物成环修饰方面的进展,重点介绍若干具有优良抗菌活性的新化合物以及相关的构效关系信息。     

新型红霉素类大环内酯衍生物的合成及抗菌活性研究

目的 对大环内酯类抗生素进行结构改造，拟筛选获得抗菌活性更高的候选药物；方法 分别对氟红霉素和克拉霉素的C-3及C-11，C-12进行结构修饰，设计合成了17个大环内酯类衍生物，采用微量稀释法测定了衍生物的最低抑菌浓度(MIC)。结果 12d、12e和12f对B. subtilis 168和 S. aureus USA 300表现出了较好的抗菌活性；结论 通过结构改造获得了抗菌活性增强的大环内酯类衍生物，进一步探讨了大环内酯类抗生素的构效关系，为后续研究提供了参考。     

红霉素衍生物的研究进展

红霉素A是目前临床常用的大环内酯类抗生素,但由于抗菌谱窄、酸稳定性差,其应用受到限制。第二代大环内酯类抗生素具有良好的抗菌活性和酸稳定性,但是目前耐药性问题成为当务之急。本文主要综述了目前红霉素结构改造的研究进展,为解决耐药性问题提供良好途径。     

新一代红霉素衍生物及其构效关系研究进展

综述国内外关于十四元大环内酯类抗生素红霉素的结构修饰和所得衍生物抗菌活性的研究近况,介绍了若干个有较好抗菌活性的先导化合物。大环内酯类抗生素广泛应用于临床的同时,细菌对其产生耐药性的问题也愈发突出。以酮内酯为代表的新一代大环内酯类红霉素衍生物具有良好的药动学性质,且对耐药菌有很好的活性,成为近年来大环内酯类抗生素研发的重点。     

大环内酯类抗生素及其临床应用进展

目的综述大环内酯类抗生素及其临床应用进展。方法查阅文献资料,从大环内酯类抗生素的作用机制及耐药性、不良反应、临床应用进展概括大环内酯类抗生素及其临床应用进展。结果大环内酯类抗生素有抗茵作用以外的药理作用及临床新用途。结论第三代大环内酯类抗生素抗茵谱扩大,半衰期延长,不良反应少。     

酮内酯类抗生素——泰利霉素和喹红霉素的化学合成

近年来人们研制出一种新的大环内酯类抗生素,即酮内酯类抗生素。第一代红霉素由于对胃酸的不稳定性,致使了第二代的阿奇霉素、罗红霉素等的出现,而且取得了很好的临床效果。但是近年来抗菌形势更加严峻,促使了第三代酮内酯类的研发,其代表药物为泰利霉素(HMR-3647)和喹红霉素(ABT-773),本文就其合成路线、药效学、构效关系等一一加以介绍。     

Recent advances in the field of 16-membered macrolide antibiotics

The continuing emergence of bacterial resistance has provided an incentive for recent intensified research on macrolide antibiotics. Belonging to the macrolide family, 16-membered macrolides also experience a renewed interest in further exploration. The medicinal potential of 16-membered macrolides in search for new antibacterials stems from some advantages over 14-membered macrolides, such as gastrointestinal tolerability, structural flexibility, and lack of inducible resistance. Thus, compared with abundant articles on various 14-membered macrolide derivatives in the literature, this review will highlight some representative 16-membered macrolide antibiotics and their recently discovered analogs. Furthermore, the action and resistance mechanisms of 16-membered macrolide antibiotics will be elucidated as well to assist the drug design.     

The role of efflux in macrolide resistance

Efflux is one of the major resistance mechanisms for macrolide antibiotics observed in both laboratory and clinical settings. This review summarizes the recent research on two major macrolide efflux pumps: Mef in Gram-positive organisms and Acr-AB-TolC in Haemophilus influenzae and Escherichia coli. The roles of pumps in macrolide resistance and the new advances / strategies to overcome efflux are discussed.     

Macrolide antibiotics: binding site,mechanism of action,resistance

Macrolides are among the most clinically important antibiotics. However, many aspects of macrolide action and resistance remain obscure. In this review we summarize the current knowledge, as well as unsolved questions, regarding the principles of macrolide binding to the large ribosomal subunit and the mechanism of drug action. Two mechanisms of macrolide resistance, inducible expression of Erm methyltransferase and peptide-mediated resistance, appear to depend on specific interactions between the ribosome-bound macrolide molecule and the nascent peptide. The similarity between these mechanisms and their relation to the general mode of macrolide action is discussed and the discrepancies between currently available data are highlighted.     

3D-QSAR and molecular docking for the discovery of ketolide derivatives

Introduction: There is an urgent need to discover novel antibiotics to overcome the growing problem of antibiotic resistance, which has become a serious concern in current medicine. Ketolides, the third generation of macrolide antibiotics, have shown promising effect against macrolide-resistant pathogens in respiratory diseases. Currently, a number of ketolide derivatives with excellent antibacterial activities have been reported, while their structure–activity relationships (SARs) were rarely explored systematically. Computer-aided drug design (CADD) such as 3D-QSAR and molecular docking are useful tools to study drug SARs in medicinal chemistry. Using these technologies, ketolide derivatives were systemically analyzed revealing important useful information about their SARs, providing useful information which can guide new drug design and optimization.

Areas covered: The authors provide an overview of the currently reported 3D-QSAR models of ketolide derivatives. The authors present a comprehensive SAR model obtained from in-depth 3D-QSAR and molecular docking analysis for all kinds of ketolide derivatives.

Expert opinion: 3D-QSAR has been shown to be a reliable tool that had successfully assisted the design of several new antibiotics with improved activity and reduced toxicity. By applying 3D-QSAR and molecular docking, a comprehensive and systematic SAR model for ketolide derivative discovery was formed, which is important to guide future drug design for the discovery of better ketolides with lower toxicity.     

Macrolide resistance mechanisms in Gram-positive cocci

Two principal mechanisms of resistance to macrolides have been identified in Gram-positive bacteria. Erythromycin-resistant methylase is encoded by erm genes. Resultant structural changes to rRNA prevent macrolide binding and allow synthesis of bacterial proteins to continue. Presence of the erm gene results in high-level resistance. Modification of the mechanism whereby antibiotics are eliminated from the bacteria also brings about resistance. Bacteria carrying the gene encoding macrolide efflux (i.e. the mefE gene) display relatively low-level resistance. Azithromycin, because of its ability to achieve concentrations at sites of infections, is capable of eradicating mefE-carrying strains. Other resistance mechanisms, involving stimulation of enzymatic degradation, appear not to be clinically significant.     

大环内酯糖基转移酶研究进展

在临床上得到广泛应用的大环内酯类抗生素的合成中，糖基化反应对其发挥生物功能十分重要，同时大环内酯糖基化也是一种微生物产生抗生素抗性的重要手段。这些糖基化反应是由一种被称为糖基转移酶(GTase)的蛋白催化完成的，对大环内酯GTase结构、功能和应用领域的研究将为组合生物学研究奠定坚实的基础。本文详细介绍了大环内酯糖基化的生物功能，并对大环内酯GTase的分类和发现情况作了深入讨论。随后回顾了大环内酯糖基化产生的抗性机制，并对相应的GTase MGT进行了细致的介绍。依据大环内酯GTase具有灵活底物特异性的特点，认真总结了其在组合生物学领域的应用情况。最后，作者根据本课题组的相关研究成果，对大环内酯GTase的应用前景进行了展望。     

Natural and acquired macrolide resistance in mycobacteria

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.     

Ketolides: the future of the macrolides?

The prevalence of antibiotic resistance in bacterial pathogens associated with community-acquired respiratory tract infections is increasing. Ketolides, semi-synthetic derivatives of erythromycin, overcome the macrolide resistance mechanisms found in Streptococcus pneumoniae and Streptococcus pyogenes, two key pathogens. They also have improved potency and longer post-antibiotic effects, while maintaining the antibacterial spectrum of the macrolide class. The new ketolides cethromycin (ABT-773) and telithromycin have overall antibacterial properties that suggest they will be clinically useful new antibiotics and are undergoing clinical development and regulatory review.     

Inactivation of macrolides by producers and pathogens

Inactivation, one of the mechanisms of resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, appears to be fairly rare in clinical isolates in comparison with target site modification or efflux. However, inactivation is one of the major mechanisms through which macrolide-producing organisms avoid self-damage during antibiotic biosynthesis. The inactivation mechanisms for MLS antibiotics in pathogens are mainly hydrolysis, phosphorylation, glycosylation, reduction, deacylation, nucleotidylation, and acetylation. The ere (erythromycin resistance esterase) and mph (macrolide phosphotransferase) genes were originally found in Escherichia coli. Subsequently, Wondrack et al. (Wondrack, L.; Massa, M.; Yang, B.V.; Sutcliffe, J. Antimicrob. Agents Chemother., 1996, 40, 992) reported ere-like activity in Staphylococcus aureus. In addition, a variant of erythromycin esterase was found in Pseudomonas sp. from aquaculture sediment by Kim et al. (Kim, Y.H.; Cha, C.J.; Cerniglia, C.E. FEMS Microbiol. Lett., 2002, 210, 239). Although the mph genes, including mph(K), were first characterized in E. coli, a recent study revealed that S. aureus and Stenotrophomonas maltophilia have mph(C). The mph(C) has a low G+C content, like mph(B), and has high homology with mph(B), but not with mph(A) or mph(K). Consequently, the mph(C) and ere(B) genes seem to have originated from Gram-positive bacteria and been transferred between Gram-positive and Gram-negative bacteria. In this chapter, the genes and the mechanisms involved in the inactivation of MLS antibiotics by antibiotic-producing bacteria are reviewed.     

The emerging new generation of antibiotic: ketolides

The bacterial ribosome is a target for a variety of drug classes including macrolides. Macrolide antibiotics are primarily used for the treatment of respiratory tract infections. One of the most important features of the macrolide class is the excellent safety profile allowing the drug to be used broadly across all age groups. The emergence of macrolide resistance, especially in S. pneumoniae, threatens the long-term usefulness of macrolide antibiotics. The newly developed ketolide class, including telithromycin and ABT-773, evolved from the macrolide class and displays significant improvements over macrolides while maintaining safety profiles similar to macrolides. The key improvement in antimicrobial spectrum is the in vitro potency against macrolide resistant pathogens, especially S. pneumoniae. This review outlines the key improvements of ketolides over macrolides in terms of in vitro microbiology, as well as the pharmacokinetic and pharmacodynamic profiles and updates the current understanding of drug-ribosome interactions. The application of cutting-edge technology such as ribosome structure-based rational drug design and genetic engineering are also briefly discussed.