治疗革兰氏阳性细菌感染药物的研究现状与进展

近年来抗革兰氏阳性耐药菌的新药研究受到关注。有四种主要抗革兰氏阳性耐药菌的新药上市：一批具有良好抗革兰氏阳性菌作用的广谱抗菌药临床应用；还有若干颇具开发前景的化合物正在研究中。本文简要综述了新型结构、新作用机制(或新作用靶位)的抗菌药研究；抗生家与抗菌药的结构修饰；增强与保护抗菌药性能的物质研究等三个方面进展。     

抗菌药物研究进展

综述了近年来抗菌药研究进展。全文分三个部分。在第一部分中叙述了奖孢菌素、碳青霉烯、青霉烯、氨基糖苷、大环内脂、四环素和抗MRSA、PRSP、VRE等革兰氏阳性耐药菌的抗生素研究进展。第二部分介绍喹诺酮类、恶唑酮类与其他新合成抗菌药研究概况，最后评述了值得注意的研究动向：近年来，为了治疗需要，除致力于筛选对耐药菌有效的、具有新抗菌谱、新作用机制、新作用靶位的抗菌药外，还注意寻找提高与保护抗菌药物效能的物质，如抗生素增强剂、抗生素灭活酶抑制剂、渗透性促进剂、外排泵抑制剂等。并努力探索增强机体防御机能与阻断微生物感染途径与衰减病原性的物质。     

铜绿假单胞菌对碳青霉烯类抗生素的耐药性

铜绿假单胞菌因其固有与获得性耐药，使抗菌药物的选择成为困惑医师的一大难题。碳青霉烯类抗生素由于其独特的抗菌优势受到临床医师的青睐，但随着使用的日益广泛，耐碳青霉烯类的铜绿假单胞菌也日益增多。铜绿假单胞菌对碳青霉烯类抗生素主要存在以下几种耐药机理：①β-内酰胺酶的水解作用（碳青霉烯酶、AmpC酶和ESBLs）；②外膜通透性下降（OprD2突变或缺失）；③主动外排机制；④改变抗菌药物作用的靶位。铜绿假单胞菌对抗生素的耐药往往不是由单一因素造成的，且不同碳青霉烯类抗生素之间耐药机制存在差异。     

正处临床开发阶段的新药：注射用杀菌性糖肽类抗生素Telavancin

抗生素的广泛应用导致了多药耐药的革兰阳性致病菌的出现，如耐甲氧西林金葡菌（麟）、中高度耐药金葡菌、耐青霉素肺炎双球菌（ease）及耐万古霉素肠球菌（Ⅵ也）等，使临床上对新型有效抗菌剂的需求与日俱增。虽然目前上市的linezo-lid和quinuprisfin／dalfopristin等抗菌剂能有效对抗某些耐药菌，但是它们会产生新的耐药性和副作用。因此，研究人员正致力于开发更具活性的抗耐药菌药物。     

新的抗革兰阳性菌抗生素的药物经济学

革兰阳性耐药菌,如耐甲氧西林金葡菌(MRSA)、耐万古霉素肠球菌(VRE)和耐青霉素肺炎链球菌感染等已经成为临床医师必需经常面对的棘手问题,这也迫使药物化学家加快了研制能有效对付这些革兰阳性耐药菌感染的新抗生素的步伐.本文根据近年来已上市和即将上市的新抗生素(包括氟喹诺酮类、脂肽类、噁唑烷酮类和糖肽类等)的生物学性质(如抗菌谱、抗菌活性、耐药性,疗效、作用靶点和安全性)的不同以及临床医师在选择治疗方案时必须考虑的其他各种因素,对这些新药在治疗革兰阳性耐药菌感染时的药物经济学及其彼此的差异进行了综述,为临床医师选择最佳治疗方案提供参考.     

多重耐药菌

多重耐药菌（Multidrug—Resistant Organism,MDRO）,主要是指对临床使用的三类或三类以上抗菌药物同时呈现耐药的细菌。常见多重耐药菌包括耐甲氧西林金黄色葡萄球菌（MRSA）、耐万古霉素肠球菌（VRE）、产超广谱β－内酰胺酶（ESBLs）细菌、耐碳青霉烯类抗菌药物肠杆菌科细菌（CRE）、耐碳青霉烯类抗菌药物鲍曼不动杆菌（CR—AB）、多重耐药／泛耐药铜绿假单胞菌（MDR／PDR—PA）和多重耐药结核分枝杆菌等。     

抗菌药物临床应用与致病菌耐药及相关性研究

目的探讨我院抗菌药物的使用与常见致病菌耐药趋势及相关因素，为临床合理用药提供依据。方法统计分析2008年1至12月住院患者抗菌药物的使用及同期临床检出常见致病菌的耐药情况。结果抗菌药物使用率为85．9％，不合理用药率38．5％，第三代头孢类药物用药频度位居首位且大部分药物用药系数〉1，头孢类、喹诺酮类、青霉素类是临床用药主流；大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌、金黄色葡萄球菌、凝固酶阴性葡萄球菌为我院临床常见致病菌，耐甲氧西林凝固酶阴性葡萄球菌分离率（79．9％）大于耐甲氧西林金黄色葡萄球菌（60．5％）；不同细菌对常见抗菌药物呈现不同程度的耐药性，头孢类耐药率为28．4％-98．3％、喹诺酮类耐药率为37．8％-82．7％、青霉素类耐药率为71．9％-100％，亚胺培南耐药率最低（〈10％）、氨苄西林耐药率最高（〉98％），阿米卡星比较敏感，磷霉素耐药率相对较低（〈40％）；抗菌药物耐药率与其用药频度、预防用药程度呈正相关（r=0．927、0．973，P〈0．01）。结论抗菌药物有一定的滥用倾向，致病菌耐药率与抗菌药物的不规范使用程度呈正相关，加强抗菌药物应用管理、合理使用抗菌药物是降低细菌耐药的关键。     

结核病：现行治疗和新药开发

结核病的控制很复杂，有长期化学治疗的困难、潜伏细菌不能消除和结核分支杆菌产生多药耐药菌株等问题。迫切需要能控制结核病的新药，包括开发短程抗生素疗法以减少药物耐药的发生，治疗多药耐药的结核菌株和根除潜伏细菌的新药。近年来见证了许多新结构类型的抗分支杆菌新药，一些药对敏感和耐药结核菌均呈现有希望的活性。尤其是新发现的二芳基喹啉具有较佳抗结核菌活性，硝基咪唑并吡喃最近研究结果令人鼓舞和独特的嚼唑烷酮也很有意义。分支杆菌基因组学的成功促进遗传学和生化研究深入了解菌壁生物合成和代谢过程，揭示了许多潜在的药物靶标。     

磷霉素治疗临床耐药菌感染

目的：介绍磷霉素治疗临床耐药菌感染的现状。方法：对国内外近年的相关文献进行分析、归纳。结果：磷霉素与其他抗菌药物合理联用可有效治疗某些耐药菌感染。结论：磷霉素与头孢菌素类、氨基糖苷类、喹诺酮类等抗菌药物联合应用对耐甲氧青霉素金葡萄菌（MRSA）,耐青霉素肺炎球菌,多耐性铜绿假单胞菌（MDRP）以及耐药痢疾志贺菌等有良好的协同作用,是治疗临床耐药菌感染的较佳选择。     

耐亚胺培南的铜绿假单胞菌和鲍曼不动杆菌的耐药性分析

目的探讨耐亚胺培南的铜绿假单胞菌和鲍曼不动杆菌的临床分布及耐药特性。方法常规方法进行菌株分离，经革兰染色、氧化酶试验等初筛，再经VITEK-32型全自动微生物分析仪进行菌株鉴定和药敏试验，部分药敏采用KB法。结果2005年6月至2006年12月分别检测到42株耐亚胺培南的铜绿假单胞菌和30株耐亚胺培南的鲍曼不动杆菌，标本来源主要为痰液，占75．0％（54／72），其次为伤口分泌物8．3％（6／72）。耐亚胺培南的铜绿假单胞菌和鲍曼不动杆菌病区分布前4位的是呼吸内科（45．8％）、神经内科（23．6％）、血液内科（18．1％）和神经外科（9．7％）。耐亚胺培南铜绿假单胞菌对常用17种抗菌药物耐蕴率〉50％的有11种，其中耐药率〉90％的也有7种，分别为氨苄西林、氨苄西林／舒巴坦、头孢唑林、头孢替坦、头孢曲松、复方磺胺甲唑和呋喃妥因，耐药率较低的有妥布霉素（11．9％）、阿米卡星（13．3％）和庆大霉素（21．7％）。耐亚胺培南鲍曼不动杆菌对常用的17种抗菌药物耐药率最低的为头孢哌酮／舒巴坦（16．7％），对其余16种抗菌药物的耐药率均〉80％。结论耐亚胺培南的铜绿假单胞菌和鲍曼不动杆菌的多重耐药性严重，临床可根据药敏试验选用抗菌药物，在本文条件下耐亚胺培南鲍曼不动杆菌建议选用头孢哌酮／舒巴坦；耐亚胺培南的铜绿假单胞菌建议选用妥布霉素、阿米卡星和庆大霉素。     

40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

The 40th ICAAC Meeting provided one of the widest varieties of new antibacterial and antifungal agents in years, with a range of improved ‘classical’ agents (Β-lactams, carbapenems), novel quinolone agents and totally new ideas for novel therapeutic intervention. Among the compounds reported were potent anti-MRSA carbapenems, novel des-fluoroquinolones (BMS 284756/T-3811), non-fluorinated quinolones, quinolone-related antibacterials, novel cephalosporins (cefditoren, RWJ-54428, MC 04546), ketolides (telithromycin, ABT-773), novel streptogramins and novel Β-lactamase inhibitors, bacterial and fungal efflux pump inhibitors and novel antifungals (azasordarins, echinocandins, azoles).     

New strategies for antibacterial drug design: targeting non-multiplying latent bacteria

During the past two decades, the number of antibacterials that has reached the marketplace each year has declined, whilst resistance to existing antibacterials has increased. New antibacterials are needed to replace those that have become less effective as a result of the emergence of a high level of resistance amongst target bacteria. Antibacterials are developed by targeting live multiplying whole bacterial cells, or essential bacterial molecules such as enzymes. Using these targets, libraries of natural, recombinant or chemically synthesised compounds are screened. Most existing antibacterials have been developed by creating novel analogues of established antibacterials, which are themselves derivatives of natural compounds. Recently, live non-multiplying bacteria have been used as targets. Bacteria in such a phase are much more tolerant to antibacterials than logarithmic phase organisms. Targeting of non-multiplying bacteria has the potential to yield new antibacterials that would shorten the duration of therapy. This would be more convenient for the patient, could reduce the incidence of adverse effects of treatment, and might reduce the emergence of antibacterial resistance. However, there is much to learn about non-multiplying bacteria, particularly the mechanisms that lie behind their profound antibacterial tolerance. New terminology has been proposed for susceptibility tests for antibacterial agents against non-multiplying bacteria, namely: the minimum stationary-cidal concentration and the minimum dormicidal concentration, which are defined as the minimum concentrations of drug that will kill stationary and dormant bacteria, respectively. The relationship between the antibiotic susceptibility of stationary and logarithmic phase bacteria is the stationary/logarithmic ratio. This terminology is suitable for both planktonic and biofilm cultures. In the future, it is likely that most antibacterial drug design will be based on existing antibacterial structures, but an increasing number of new molecular antibacterial structures may emerge from screening against multiplying and perhaps non-multiplying bacteria. The genomic approach has been disappointing so far, but it is still hoped that this will produce novel antibacterial agents.     

The millennium bugs--the need for and development of new antibacterials

Global antibacterial resistance is becoming an increasing public health problem. Bacteria resistant to almost all of the available antibacterials have been identified. The pharmaceutical industry and fledgling biotechnology companies are responding to the threat of antibiotic resistance with renewed efforts to discover novel antibacterials in attempts to overcome bacterial resistance. Both short term and long term strategies are being vigorously pursued. Short-term efforts are focused on developing novel antibacterial agents with a narrow spectrum of action to combat the problem of gram-positive resistant bacteria. Long-term approaches include the use of microbial genomic sequencing techniques to discover novel agents active against potentially new bacterial targets. Better use of existing agents using pharmacodynamic data to optimise antibiotic regimens is increasingly being addressed and the hope is that such measures will prevail until the newer agents are available.     

Antibacterial agents: patent highlights July to December 2002

Forty-five patents dealing with disclosures on the different classes of antibacterial agents, reported between July and December 2002, are selected for review. Disclosures dealing with novel derivatives of known antibacterials (beta-lactam, oxazolidinone, macrolide, quinolone, tetracycline and peptide derivatives), development of new processes and formulations to improve cost, activity and stability are highlighted. In addition, patent disclosures on novel oxazolidinone derivatives with broad-spectrum activity extended against fastidious Gram-negative bacilli are highlighted in comparison to linezolid. Novel antibacterial agents (peptide-deformylase inhibitors) that could serve as potential lead compounds are also presented.     

Hybrid antibacterials. DNA polymerase-topoisomerase inhibitors

Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.     

Structure-based design, synthesis, and study of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.     

When will the genomics investment pay off for antibacterial discovery?

Effective solutions to antibacterial resistance are among the key unmet medical needs driving the antibacterial industry. A major thrust in a number of companies is the development of agents with new modes of action in order to bypass the increasing emergence of antibacterial resistance. However, few antibacterials marketed in the last 30 years have novel modes of action. Most recently, genomics and target-based screening technologies have been emphasized as a means to facilitate this and expedite the antibacterial discovery process. And although no new antibacterials have yet been marketed as result of these technologies, genomics has delivered well-validated novel bacterial targets as well as a host of genetic approaches to support the antibacterial discovery process. Likewise, high throughput screening technologies have delivered the capacity to perform robust screenings of large compound collections to identify target inhibitors for lead generation. One of the principal challenges still facing antibacterial discovery is to become proficient at optimizing target inhibitors into broad-spectrum antibacterials with appropriate in vivo properties. Genomics-based technologies clearly have the potential for additional application throughout the discovery process especially in the areas of structural biology and safety assessment.     

The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram‐negative bacteria. The T3SS consists of structural proteins, effectors, and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non‐infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins, and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design.     

Tigecycline: a case study

The emergence of pathogenic bacteria resistant to virtually all available antibacterial agents at present has caused consternation among medical professionals, but has only intermittently raised concern among the public. This has led to a transient resurgence of interest in studying the mechanisms of resistance and in discovering and developing new antibacterial agents, but successes in the development of novel antibacterial agents have been few and far between. Although it has been known since the discovery of the tetracyclines that they are inhibitors of protein synthesis, there has been considerable recent progress on elucidating the mechanisms of action of the tetracyclines and in the enhanced understanding of the mechanisms of tetracycline resistance. In this case study, the authors discuss the discovery and development of a new class of antibacterials, which were derived from the tetracyclines, namely the glycylcyclines. This has resulted in the introduction of a new agent, tigecycline, to clinical practice. The glycylcyclines restore the antibacterial activity to levels of the earlier tetracyclines when they were first introduced, by overcoming the two major tetracycline-resistance mechanisms of efflux and ribosome protection, which promises to have a high degree of clinical utility.     

Recent advances in the discovery and development of quinolones and analogs as antitumor agents

Compounds that interact with DNA or microtubules by multiple mechanisms and cause diverse cytotoxic lesions are potential targets for anticancer drug development. Accordingly, a relatively new approach to the rational design of antitumor agents is based on the quinolone class of antibacterials. Their mechanism of antibacterial action involves inhibition of DNA gyrase, and numerous new quinolones do exhibit antitumor activity. Thus, these new quinolone structures display a novel mode of action for the quinolone class as antitumor agents. The potential for quinolones to be used as topoisomerase II inhibitors, as well as antimitotic agents, is reviewed with a focus on recent discoveries and development of antitumor quinolones, especially related work in the author's laboratory.