全球关注：重视抗生素发展与耐药风险的对策

随着抗生素的广泛使用甚至滥用，目前细菌对抗生素的耐药性问题已十分严重，抗生素耐药性正在对全球健康和社 会经济负担构成威胁。因此全球关注和重视抗生素发展与耐药风险的对策已经成为共识的世界大事。本文结合全球关注的社会 (包括国际组织、政府、企业、学术团体、公众、医护和患者)重视抗生素的发展和耐药性的对策的现状， 从抗生素发展与风险 并存、新抗生素研发受阻和全球抗生素滥用与耐药问题亟需解决3方面予以阐述。同时关注质量创新理念的发展，认识从“质 量源于检验”到“质量源于设计”革命在质量提高中的重要性。     

Inhibiting conjugation as a tool in the fight against antibiotic resistance

Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.     

联合用药：未来抗菌药物研发的趋势

摘要：抗菌药物的大量使用使得菌株出现耐药性,耐药性的出现给人类和现代医学造成巨大威胁。几十年来,抗菌药物新药的开发十分困难。近年来,抗菌药物组合药物不断发展,抗菌药物和具有非抗菌药物活性化合物的组合,不仅延长了老抗菌药物的使用寿命,引入的非抗菌药物活性化合物也有效应对抗菌药物新药开发困难的局势。组合的应用为解决广泛出现的耐药性提供了一种有效的策略,本文综述了近年来抗菌药物组合的发展,详细介绍了抗菌药物与非抗菌药物活性化合物组合的实例以及对抗菌药物新药研发的指导。     

Reducing the development of antibiotic resistance in critical care units

Bacteria becoming resistant to an increasing number of antibiotic classes are a major problem at hospitals including critical care units worldwide. Awareness of this problem and the need to prevent the development of antibiotic resistance are very important, especially since very few new antibiotics will become available in the near future. This article gives an overview of the mechanisms of antibacterial resistance and actual resistance data worldwide of the most prevalent Gram positive (MRSA, VISA/VRSE and VRE) and Gram negative bacteria (Pseudomonas aeruginosa, Acinetobacter spp., ESBL producing Enterobacteriaceae and Stenotrophomonas maltophilia). Furthermore, strategies to reduce antibiotic resistance are reviewed. Most important is institution of infection control policies including guidelines on surveillance, isolation of colonized patients and contact precautions, hand hygiene, decolonization measures and environmental decontamination. Antimicrobial stewardship, or striking the balance between an optimal antibiotic treatment for a patient and a minimal risk of development of antibiotic resistance, is another important strategy. Finally, optimizing of antibiotic dosage regimens and thus avoiding underdosage is essential to avoid selection of the most resistant subpopulation of bacteria during antibiotic treatment. Intensive care units with knowledge of local epidemiology of resistance, an effective infection control program and antimicrobial stewardship policy tailored to their specific needs, and using optimal antibiotic dosing regimens have both locally decreased the risk of an outbreak with multi-resistant bacteria, and maybe even more important help to reduce the development of antibiotic resistance.     

Recent progress toward the clinical development of new anti-MRSA antibiotics

The escalation in drug resistance is well documented for methicillin-resistant Staphylococcus aureus (MRSA) and the urgency to discover new antibiotic treatments is more apparent with the growing incidences of vancomycin-intermediate and vancomycin-resistant S aureus. Much of the current research into finding new remedies focuses on chemical modification of existing antibiotics (ie, glycopeptides and cephalosporins) and developing synthetic molecules with novel mechanisms of action (ie, oxazolidinones and N-thiolated b-lactams). This review describes recent progress toward the clinical development of new drug therapies for MRSA.     

基因研究在抗生素耐药中的应用

随着抗生素的广泛使用,诸多病原菌产生了耐药性。耐药问题已成为二十一世纪人类面临的最严峻的环境健康问题之一,受到了诸多研究者的关注。目前,新型抗生素研发、现有抗生素改良以及阐明微生物的耐药机制等研究正在不断的开展。基因组学的不断发展为病原菌耐药性研究带来了极大的便捷,高通量测序技术结合分子生物学技术构建了多种抗生素抗性基因数据库及分析工具,这极有利于研究者高效地发现各种新的耐药基因,了解耐药性产生的原因与发展过程。本综述的目的在于从基因的视角认识病原菌耐药性,为科学研究及临床工作中更好的理解和应对耐药问题提供便利。     

Clinical pharmacology of antimicrobial use in humans and animals

Veterinary public health is a frontier in the fight against human disease, charged to control and eradicate zoonotic diseases that are naturally transmitted between vertebrate animals and man. Currently there is a need for clinical pharmacologists and all health care givers to limit the development of bacterial resistance in humans to contain the increased health care expenditures related to morbidity and mortality associated with the use of antimicrobials. The development of resistance predates the use of antibiotics and will always be a problem to the successful treatment of patients. Ongoing discussion debates the extent to which antibiotic use in animals contributes to the development of antibiotic resistance in humans. The veterinary use ofantibiotics as antimicrobial growth promoters is thought to influence the prevalence of resistance in animal bacteria and to be a risk factor for the emergence of antibiotic resistance in human pathogens. Transfer of antibiotic resistant bacteria from animals to humans may occur via contact, including occupational exposure and via the food chain. Resistance genes may transferfrom bacteria of animals to human pathogens in the intestinal flora of humans. Prevention of the development of resistance in humans necessitates good animal husbandry and hygienic measures to prevent cross contamination and a decrease in the use of antibiotics. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. Investigators must also develop new antimicrobial agents. Poole (J Pharmacy Pharmacol 2001;53:283) recommends targeting the three predominate mechanisms of development of resistance by antimicrobials (i.e., antibiotic inactivation, target site modification, and altered uptake via restricted entry and/or enhanced efflux) to specifically complement the development of novel agents with novel bacterial targets. Bacterial resistance and its selection may be evaluated by comparing the relationship to antibiotic pharmacokinetic (PK) values obtained from serum concentrations and organism MICs (minimum inhibitory concentrations; concentration-dependent killing) to reveal culture and sensitivity tests in patients. Pharmacodynamic (PD) models may be developed to identify factors associated with the probability that bacterial resistance will develop. Thomas et al (Antimicrobial Agents Chemotherapy 1998;42:521) used this combined approach of PK/PD and MICs to examine data retrospectively. The role of clinical pharmacology is to work with PK/PD models such as these to determine the best use of antibiotics in humans to minimize the development of resistance. The role of any regulatory body responsible for the protection of the public health and food safety for consumers is to assess risk and to then communicate and manage the risk. Scientific uncertainty must be interpreted to propose sound policy options. The conversion of sound science into an appropriate regulatory policy to protect the public health is most important.     

Dual-acting hybrid antibiotics: a promising strategy to combat bacterial resistance

Importance of the field: The emerging and sustained resistance to currently available antibiotics and the poor pipeline of new antibacterials urgently call for the development of new strategies that can address the problem of growing antibacterial resistance. One such strategy is the development of dual-action hybrid antibiotics: two antibiotics that inhibit dissimilar targets in a bacterial cell covalently linked into one molecule. The possible benefits include: i) activity against drug-resistant bacteria, ii) expanded spectrum of activity and iii) reduced potential for generating bacterial resistance. Areas covered in this review: In this article, we detail the recent activity in the design and development of dual-action hybrid drugs with a non-cleavable linker. We explore newly developed synergistic and antagonistic hybrid compounds with emphases on their potential to reduce resistance development. What the reader will gain: Recently developed synergistic and antagonistic antibacterial drug-drug interactions and the impact of such interactions on the evolution of antibiotic drug resistance are described. Additionally, we discuss the implications of the latter observations on the development of hybrid antibiotics with the emphases on whether their synergistic or antagonistic effect will be more efficient at forestalling/reducing the development of new resistances. Take home message: The approach of dual-acting hybrid antibiotics holds significant current promise in overcoming existing resistance mechanisms, as three of such compounds are entering clinical trials. However, the key challenge in this area should be a broader experimental demonstration of whether the "synergistic effect" or the "antagonistic effect" of the developed hybrid drug is better at preventing/reducing the evolution of resistance. This fundamental challenge must be overcome before yielding a successful drug.     

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.     

Antimicrobial peptides: Their physicochemical properties and therapeutic application

Antibiotic resistance has become a global public health problem, thus there is a need to develop a new class of antibiotics. Natural antimicrobial peptides have got an increasing attention as potential therapeutic agents. Antimicrobial peptides are small cationic peptides with broad antimicrobial activity. They can serve as critical defense molecules protecting the host from the invasion of bacteria. Even though they possess a different mode of action compared to traditional antibiotics, antimicrobial peptides couldn’t go into the drug markets because of problems in application such as toxicity, susceptibility to proteolysis, manufacturing cost, size, and molecular size. Nevertheless, antimicrobial peptides can be new hope in developing novel, effective and safe therapeutics without antibiotic resistance. Thus, it is necessary to discover new antimicrobial sources in nature and study their structures and physicochemical properties more in depth.     

利奈唑胺C环结构改造研究进展

首个噁唑烷酮类抗菌药利奈唑胺自2000年上市以来,其耐药性问题日趋严重,开发新型噁唑烷酮类抗菌药物成为研究热点之一。综述了近年来对利奈唑胺C环进行的结构改造及相关衍生物的研究进展,旨在为噁唑烷酮类抗菌药的深入研发提供参考。     

Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view

The efflux systems of bacteria protect cells from antibiotics and biocides by actively transporting compounds out of the cytoplasm and/or periplasm and thereby limit their steady-state accumulation at their site(s) of action. The impact of efflux systems on the efficacy of antibiotics used in human medicine and animal husbandry is becoming increasingly apparent from the characterization of drug-resistant strains with altered drug efflux properties. In most instances, efflux-mediated antibiotic resistance arises from mutational events that result in their elevated expression and, in the case of efflux pumps with broad substrate specificity, can confer multi-drug resistance (MDR) to structurally unrelated antibiotics. Knowledge of the role of efflux systems in conferring antibiotic resistance has now been successfully exploited in the pharmaceutical industry and contributed, in part, to the development of new members of the macrolide and tetracycline classes of antibiotics that circumvent the efflux-based resistance mechanisms that have limited the clinical utility of their progenitors. The therapeutic utility of compounds that inhibit bacterial drug efflux pumps and therein potentiate the activity of a co-administered antibiotic agent remains to be validated in the clinical setting, but the approach holds promise for the future in improving the efficacy and/or extending the clinical utility of existing antibiotics. This review discusses the potential of further exploiting the knowledge of efflux-mediated antibiotic resistance in bacteria toward the discovery and development of new chemotherapeutic agents.     

Antibiotic resistance: an editorial review with recommendations

Within a relatively short period of time after the first antimicrobial drugs were introduced, bacteria began exhibiting varying degrees of resistance. The excessive use (and abuse) of antibiotics in agriculture, and in both human and veterinary medicine, has played a critical causative role in the development of antibiotic resistance, which is now recognized as a global public health threat. Increasing concern over this issue should impact the practice of cutaneous medicine and surgery, as dermatologists can easily adopt new healthcare delivery patterns that might reduce the development of antibiotic resistance and still achieve acceptable treatment outcomes. Dermatologists should seriously consider any and all alternative therapies before committing to an extended course of antibiotic therapy for disease entities that are almost certainly not infectious. Conversely, dermatologists should carefully and closely adhere to dosage and duration recommendations when using antibiotics to treat a bona fide infectious disorder.     

Novel targets for antibiotics--an update

The emergence of widespread antibiotic resistance as an impediment in the treatment of bacterial diseases is of growing concern. In some instances, clinicians are left with few or no antibiotics for treatment of infections and this problem will more than likely grow in magnitude. One approach to get around the problem of antibiotic resistance is to develop new drugs with novel targets and mechanisms of action. Due to the 'newness' of these novel targets as therapeutic targets, the likelihood that resistance will initially be widespread is low. Three approaches are discussed in this overview: discovery of new essential genes that are expressed exclusively in vivo development of compounds that act on global bacterial gene regulators; and interference with virulence determinants. By exploiting virulence related attributes or genes expressed exclusively in vivo, the risk of resistance is reduced since inhibiting these products will probably alter the ecology (habitats) of these organisms rather than causing direct cell death. This might also lead to a selective targeting of pathogens with the beneficial consequence of ignoring organisms growing in their normal habitat, such as in the gastrointestinal tract or skin.     

Agricultural Applications for Antimicrobials. A Danger to Human Health: An Official Position Statement of the Society of Infectious Diseases Pharmacists

The use of antibiotics in agriculture, particularly in food‐producing animals, is pervasive and represents the overwhelming majority of antibiotic use worldwide. The link between antibiotic use in animals and antibiotic resistance in humans is unequivocal. Transmission can occur by ingesting undercooked meats harboring resistant bacteria, by direct contact of animals by animal handlers, and by various other means. Antibiotics used in aquaculture and antifungals used in horticulture are also an evolving threat to human health. Regulations aimed at decreasing the amount of antibiotics used in food production to limit the development of antibiotic resistance have recently been implemented. However, further action is needed to minimize antibiotic use in agriculture. This article describes the extent of this current problem and serves as the official position of the Society of Infectious Diseases Pharmacists on this urgent threat to human health.     

Current trends in β-lactam based β-lactamases inhibitors

The introduction of antibiotics to treat bacterial infections either by killing or blocking their growth has been accompanied by the development of resistance mechanism that allows the bacteria to survive and proliferate. In particular the successive series of β-lactams have selected several generations of β-lactamases including ESBLs, AmpC β-lactamases, KPC carbapenamases in Enterobacteriaceae, the metallo β-lactamases VIMs and IMPs, and very recently the threatening NDM-1 that confers resistance to virtually any clinically used antibiotic. The increasing use of carbapenems due to the spread of resistance to other existing antibacterial agents has facilitated the spread of resistance, especially in Acinetobacter spp. due to OXA- and metallo-carbapenemases. The pharmaceutical industry, that abandoned this field at the end of the nineties, is now trying to recover by developing some novel β-lactam antibiotics and novel β-lactamase-inhibitors, the latter to be used in combination with new as well as seasoned β-lactam antibiotics. This article provides a survey of patent and scientific literature for β-lactamase inhibitors discovered in the period 2006-2010.     

The clinical impact of macrolide resistance in pneumococcal respiratory infections

By the 1960s, several reports of bacteria with reduced susceptibility to antibiotics were published. In recent years, the problem of antibiotic resistance has magnified. In the treatment of respiratory tract infections, the development of resistance is of particular concern; 67% of antibiotic use in adults and 87% in children is for the treatment of such infections. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia and is a frequently isolated bacterial species in patients with other respiratory tract infections. Increasing levels of resistance may have important implications in the clinical setting. Physicians need to consider local susceptibility data, in addition to the pharmacokinetic and pharmacodynamic features of compounds, when selecting appropriate antibiotics for the treatment of bacterial infections.     

N-alkyl-substituted glycopeptide antibiotics

The glycopeptide antibiotic vancomycin has proved valuable in the treatment of staphylococcal and enterococcal infections, particularly those caused by strains resistant to other antibiotics. The emergence of high-level resistance to vancomycin within the enterococci, and its potential for transfer to other pathogenic Gram-positive cocci, has led to interest in developing new glycopeptide antibiotics with activity against vancomycin resistant organisms. The N-alkylated glycopeptide antibiotics, under development by Lilly Research Laboratories, represent a new series of compounds possessing these properties. The lead compound in this series, LY 333328, is reported to be in Phase I trials.     

芽孢杆菌中天然脂肽类抗生素的合成及作用机制研究进展

摘要：抗生素的发现为治疗细菌感染带来了突破性进展,但随之而来的抗生素耐药性问题也愈发严峻。在减缓抗生素耐药性进展的同时,发现新型抗生素的需求也愈发强烈。天然抗生素是新型抗生素的潜在选择,而芽孢杆菌能够产生多种具有广谱抑菌活性的细菌脂肽,包括polymyxins、surfactins、iturins、fengycins等,具有巨大的研究和开发潜力。本文综述了芽孢杆菌产生的一系列脂肽类抗生素的特征、合成及作用机制,充分展现了芽孢杆菌脂肽的应用潜力。未来可利用基因组测序技术挖掘新型脂肽类抗生素合成通路,利用基因工程及分子生物学技术提高产量,运用化学合成和化学修饰进行改良,促进芽孢杆菌中脂肽类抗生素的开发利用。     

New advances in antibiotic development and discovery

The development of new antibiotics is crucial to controlling current and future infectious diseases caused by antibiotic-resistant bacteria. Increased development costs, the difficulty in identifying new drug classes, unanticipated drug toxicities, the ease by which bacteria develop resistance to new antibiotics and the failure of many agents to address antibiotic resistance specifically, however, have all led to an overall decline in the number of antibiotics that are being introduced into clinical practice. Although there are few, if any, advances likely in the immediate future, there are agents in both clinical and preclinical development that can address some of the concerns of the infectious disease community. Many of these antibiotics will be tailored to specific infections caused by a relatively modest number of susceptible and resistant organisms.