抗菌肽抗菌机制及与抗生素协同作用的研究进展

抗菌肽(antimicrobial peptides, AMPs)是一种新型抗生素，对多种细菌，多重耐药细菌均具有抗菌活性。然而，其副作用也是制约抗菌肽研发的主要障碍。研究者使用模式细胞膜，揭示抗菌肽与细胞膜之间的作用方式，开展抗菌肽开发和筛选研究。另外，研究者还将抗菌肽与常规抗生素联合使用，可以协同提高抗菌效果。研究初步揭示了AMPs和常规抗生素之间协同作用的机制。本综述探讨了模式细胞膜在AMPs发现筛选中的应用，及AMPs和常规抗生素之间联合用药的研发现状。     

四环素类抗生素的复苏

摘要：四环素类抗生素是20世纪40年代发现的一类新型的抗生素。1948年第一个四环素类抗生素金霉素被应用于临床， 随着这类抗生素在临床和非临床上的大量使用，细菌耐药性不断增加、不可避免的不良反应以及其他新型抗生素的诞生，四环 素类抗生素的临床地位逐渐降低。20世纪70年代，第二代四环素类抗生素的米诺环素诞生了，因为其对耐药菌有效而在临床上 受到青睐。特别是在2005年，对多种耐药株具有较好活性的第三代四环素类抗生素替加环素被FDA批准上市，之后又经过了13 年，2018年FDA(Food and Drug Administration)同时批准了3种新型第三代四环素类抗生素上市，使得四环素类抗生素重新进入了 公众的视野。本文主要就第三代四环素类抗生素的抗微生物活性，化学结构特性、作用机制与抗耐药性，以及药物的临床研究 等方面进行综述。     

浅谈抗生素不合理使用的原因及对策

随着科学技术的不断进步与发展，在人类与疾病的斗争中，致病性生物菌与人类抗生素的使用一直处于一种演变与发展之中。新的抗生素不断出现和使用为感染性疾病的治疗提供了有利的武器，但同时人类长期、大量的使用抗生素，也使得致病菌对抗生素逐渐发生了适应，产生了耐药性，这将是人类面临的严峻问题。抗生素药物的不合理使用已引起了广泛关注。     

抗生素耐药与抗生素新药开发的研究进展

抗生素的发现和使用是20世纪最伟大的成就之一.随着抗生素的广泛应用,抗生素耐药成为药物使用时应重点关注的问题.抗生素耐药主要与细菌的自然选择、抗生素不合理使用有关,同时也使得抗生素新药的开发存在着诸多挑战.世界卫生组织(WHO)一直关注抗生素的危害和耐药问题,认为这些问题已经成为公共卫生和可持续医疗的最严重挑战.对抗生...     

抗生素的合理应用原则

自青霉素问世至今，抗生素的使用已经有几十年历史了。尤其随着医药科技的发展，新型抗生素不断涌现，在治疗感染性疾病方面发挥了重要的作用。但是随着抗生素的广泛使用，尤其是无原则的滥用，也带来了诸多不良后果。不仅仅是患者负担加重、毒副作用增多和医疗费用增长，而且导致细菌感染性疾病诊治困难、和细菌耐药性的产生。     

研究揭示抗生素使用和婴儿哮喘之间的联系

英国曼彻斯特大学的新研究表明，病毒导致的免疫系统受损和17号染色体遗传变异增加了早期使用抗生素治疗后哮喘发展的风险，而不是之前认为的是网为抗生素使用而导致哮喘发展。重要的是，这项研究，没有发现早期抗生素使用和过敏性疾病发展之间的联系。     

呋喃妥因作用机制与临床应用研究进展及联合用药策略

细菌耐药性的持续攀升及新型抗菌药物研发进展缓慢，使得临床抗感染治疗面临巨大挑战。早期抗生素呋喃妥因具有较强的抗菌活性和较低的临床耐药率，被重新考虑作为治疗尿路感染的一线药物，但其确切的分子作用靶点仍不清楚。本文回顾了呋喃妥因的抗菌和耐药机制、临床应用现状及联合用药研究，以期为呋喃妥因的合理使用及抗菌策略制定提供参考。     

浅谈抗生素的合理应用

自青霉素问世至今，抗生素的使用已经有几十年历史。尤其随着医药科技的发展，新型抗生素不断涌现，在治疗感染性疾病方面发挥了十分重要的作用。但是随着抗生素的广泛应用，尤其是无原则的滥用，也带来了诸多不良后果。既加重患者的经济负担，最终还可能导致临床难治性感染增多。本文就合理使用抗生素的进行讨论，旨在提高合理用药的水平。     

院内感染的发生,细菌耐药性及治疗效果与医院抗生素使用规则

对９５年度１７０例院内感染病病人在感染发生前后抗生素使用情况，细菌耐药性及治疗效果进行分析，１７０全病人中，在院内感染前，因感染使用抗生素者４２．３％，预防用抗生素者１０％。院内感染发生后，使用一种抗生素控制感染６６例，其中５７例炎未使用抗生素者，从感染患者的血，尿，粪中培养细胞２４株，真菌５株，耐３种以上抗生素有１９株，对抗生素使用进行了规定，目前无耐头孢第二代，第三代以及新型喹诺酮类药物的菌株     

临床抗生素使用调查分析

临床抗生素使用调查分析谷丽英（河北省唐山市眼科医院唐山市０６３０００）为了解临床抗生素的使用情况，我们统计了１年的住院病人共１４２４例，发现抗生素的使用有待完善。临床资料１年中使用抗生素的住院病人，共计１４２４例，其中，内科病人４５８例，眼科病人９６...     

Novel targets for antibiotics

The rapid and extensive emergence of antibiotic resistant bacteria has resulted in a clear cut need to discover new antibiotics. Because of the many years of extensive screening, it is likely that most of the easy discoveries have been made and, therefore, new targets for antibiotics and new screening strategies for their discovery need to be developed. The approaches described in this overview are divided into several categories that are associated with different probabilities for a successful discovery. Approaches that are more likely to be successful include a continuation of classical discovery tactics including the chemical modification of extant structures, the use of new screens for classical targets (for example, the use of the enzyme DNA gyrase to discover new 4-fluoroquinolones), and the development of novel methods of drug delivery. These approaches, however, are likely to yield small incremental advances. More novel approaches should yield radically new chemical structures, however, the likelihood for a successful discovery will be lower than the classical approaches. The novel approaches include rational drug design, the discovery of new essential targets for antibiotics and using them for the purpose of drug screening, and the intervention in pathways necessary for pathogenesis. A middle of the road approach is to discover new agents that interfere with mechanisms of antibiotic resistance. Implicit in this overview is the need to develop new methods that result in real technologic advances. This may require a complete re-thinking of how antibiotics are discovered including the restricted use of live microbe killing assays as a primary screening tool.     

Learnings from past failures: Future routes of antimicrobial drug discovery

Despite the unprecedented unmet need to discover new antibiotics, only a few molecules have been registered for clinical use. This shortage is primarily based on the scientific failure in the postgenomic era of drug discovery. It appears counterintuitive that knowledge of the bacterial genome was followed by the failure to produce new antibiotics using the paradigm of target-driven drug discovery. Here, I discuss the causes of the failures and also describe how small biotech is mitigating these risks and moving forward using new strategies to identify new antibiotics.     

Development of antibiotics and the future of marine microorganisms to stem the tide of antibiotic resistance

Antibiotics remain essential tools in the control of infectious diseases. With the emergence of new diseases, resistant forms of diseases such as tuberculosis and malaria, as well as the emergence of multidrug-resistant bacteria, it has become essential to develop novel antibiotics. Development of the existing antibiotics involved three strategies, including discovery of new target sites, modification of existing antibiotic structures, and the identification of new resources for novel antibiotics. Marine microorganisms have clearly become an essential new resource in the discovery of new antibiotic leads.     

Genomics strategies for antifungal drug discovery--from gene discovery to compound screening

The use of genomics tools to discover new genes, to decipher pathways or to assign a function to a gene is just beginning to have an impact. Genomics approaches have been applied to both antibacterial and antifungal target discovery in order to identify a new generation of antibiotics. This review discusses genomics approaches for antifungal drug discovery, focusing on the areas of gene discovery, target validation, and compound screening. A variety of methods to identify fungal genes of interest are discussed, as well as methods for obtaining full-length sequences of these genes. One approach is well-suited to organisms having few introns (Candida albicans), and another for organisms with many introns (Aspergillus fumigatus). To validate broad spectrum fungal targets, the yeast Saccharomyces cerevisiae was used as a model system to rapidly identify genes essential for growth and viability of the organism. Validated targets were then exploited for high-throughput compound screening.     

Use of constraint-based modeling for the prediction and validation of antimicrobial targets

The overall process of antimicrobial drug discovery and development seems simple, to cure infectious disease by identifying suitable antibiotic drugs. However, this goal has been difficult to fulfill in recent years. Despite the promise of the high-throughput innovations sparked by the genomics revolution, discovery, and development of new antibiotics has lagged in recent years exacerbating the already serious problem of evolution of antibiotic resistance. Therefore, both new antimicrobials are desperately needed as are improvements to speed up or improve nearly all steps in the process of discovering novel antibiotics and bringing these to clinical use. Another product of the genomic revolution is the modeling of metabolism using computational methodologies. Genomic-scale networks of metabolic reactions based on stoichiometry, thermodynamics and other physico-chemical constraints that emulate microbial metabolism have been developed into valuable research tools in metabolic engineering and other fields. This constraint-based modeling is predictive in identifying critical reactions, metabolites, and genes in metabolism. This is extremely useful in determining and rationalizing cellular metabolic requirements. In turn, these methods can be used to predict potential metabolic targets for antimicrobial research especially if used to increase the confidence in prioritization of metabolic targets. The many different capacities of constraint-based modeling also enable prediction of cellular response to specific inhibitors such as antibiotics and this may, ultimately find a role in drug discovery and development. Herein, we describe the principles of metabolic modeling and how they might initially be applied to antimicrobial research.     

Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships

The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.     

Carbapenem-hydrolyzing gram-negative bacteria: current options for treatment and review of drugs in development

Multidrug resistant gram-negative bacteria are an increasing therapeutic challenge. The beta-lactamases are a group of enzymes that confer resistance to the beta-lactam antibiotics. The carbapenems have been in wide use to treat beta-lactamase producing, multidrug resistant gram-negative bacterial infections. However, the emergence of carbapenemases, enzymes capable of hydrolyzing the carbapenems, has limited our therapeutic options. In the recent years, there has been some development in the discovery of new agents such as boronic acid derivatives, ME1071 and Ca-EDTA that may enhance the activity of existing antibiotics, CTC-96 which reverses antibiotic resistance and polymyxin derivatives with decreased renal toxicity. While global efforts towards new drug development should continue, appropriate use of currently available antibiotics is equally important. In this review, we will discuss the general characteristics of carbapenemases, recent patents with drugs under development and current treatment options.     

Drosophila melanogaster as a model host for the study of microbial pathogenicity and the discovery of novel antimicrobial compounds

The past few decades have seen alarming rates of antimicrobial drug resistance. This trend paralleled a lack of conventional methods of discovery of antibiotics with novel mechanisms of action. Although use of mammalian models remains indispensable for preclinical testing of new antimicrobial compounds, combating emerging multidrug-resistant microbial pathogens may require the use of robust, high-throughput experimental systems that can accelerate drug development. The recent discovery of striking similarities in innate immune signaling pathways between Drosophila melanogaster and mammals has led to a surge in the use of this minihost as an alternative model in studying a variety of infectious diseases. Several genetic screens for microbial pathogenicity in Drosophila identified virulence traits shown to be important for infection in mammals that may serve as targets for future drug development. In addition, conventional antimicrobial agents retain full activity in D. melanogaster infection models, which may pave the way for use of this minihost for high-throughput antimicrobial drug screening. Finally, the availability of genetic tools that allow for conditional inactivation of almost every gene in D. melanogaster is anticipated to result in the discovery of novel immunomodulatory mechanisms of action of newly identified antimicrobial compounds. Overall, the powerful genetics of and capacity for large-scale screening in D. melanogaster make this minihost a promising complementary model that may result in a new paradigm in antimicrobial drug discovery. However, antimicrobial drug discovery in such heterologous, phylogenetically disparate minihosts as the fruit flies, would still require further validation in mammalian models.     

Novel approaches to developing new antibiotics for bacterial infections

Antibiotics are an essential part of modern medicine. The emergence of antibiotic-resistant mutants among bacteria is seemingly inevitable, and results, within a few decades, in decreased efficacy and withdrawal of the antibiotic from widespread usage. The traditional answer to this problem has been to introduce new antibiotics that kill the resistant mutants. Unfortunately, after more than 50 years of success, the pharmaceutical industry is now producing too few antibiotics, particularly against Gram-negative organisms, to replace antibiotics that are no longer effective for many types of infection. This paper reviews possible new ways to discover novel antibiotics. The genomics route has proven to be target rich, but has not led to the introduction of a marketed antibiotic as yet. Non-culturable bacteria may be an alternative source of new antibiotics. Bacteriophages have been shown to be antibacterial in animals, and may find use in specific infectious diseases. Developing new antibiotics that target non-multiplying bacteria is another approach that may lead to drugs that reduce the emergence of antibiotic resistance and increase patient compliance by shortening the duration of antibiotic therapy. These new discovery routes have given rise to compounds that are in preclinical development, but, with one exception, have not yet entered clinical trials. For the time being, the majority of new antibiotics that reach the marketplace are likely to be structural analogues of existing families of antibiotics or new compounds, both natural and non-natural which are screened in a conventional way against live multiplying bacteria.     

基于核糖体结构和功能的新型抗生素研究进展

本文介绍了以核糖体为靶点的几种重要抗生素的作用机制,在此基础上对近几年来出现的此类药物研究的新方法新思路进行了综述。远程交互作用网络及诱导-契合机制的发现、抗生素抑制蛋白质合成的新靶点的发掘、利用计算机辅助药物设计技术及其他物理化学分析方法如分子建模技术、计算机动态模拟技术、分子对接技术、X-ray衍射技术进行新型抗生素研究,使我们对于药物与核糖体的结合方式及结合位点有了更加深入的了解,为科研人员对新型抗生素的开发和研究带来了无限的希望。