This article is part of the Antibiotics special issue. Antimicrobial resistance (AMR) has received increasing global attention over the past decade. The lack of antibiotics in the clinical pipeline is a direct result of the discouraging financial incentives for their commercial development. This has led to a precarious situation where the widespread emergence of highly resistant strains could threaten the viability of the worldwide health system, as seen with the current COVID-19 crisis. While a number of nonantibiotic alternative antimicrobial approaches show interesting potential, it is difficult to see how they would displace the need for new antibiotics for the foreseeable future. This special issue on antibiotics is a combination of viewpoints, perspectives, reviews, and original research manuscripts that provides a snapshot of the current state of affairs in antibiotic discovery and development. It is anchored by a set of 10 interrelated viewpoints and two perspectives from many of the world’s leading agencies and key opinion leaders with an interest in antimicrobial resistance. The AMR division of the World Health Organization and The Pew Trust both provide overviews of the difficulties facing antibiotic development. The WHO viewpoint summarizes its recent reports on the preclinical and clinical antibacterial pipelines, with the former showing 252 antibacterial agents being developed by 145 individual institutions and the latter including 50 antibiotics and combinations. The Pew Trust shares its progress in attempting to foster the sharing of antibiotic discovery data and knowledge and discusses how to more effectively target antibiotic discovery efforts. It urges continued early stage research funding and more coordinated action and mentions efforts to support antibiotic development by The Global Antibiotic Research and Development Partnership (GARDP) and The National Institute of Allergy and Infectious Diseases (NIAID). Both of these organizations have also provided viewpoints. GARDP outlines why it was established and what it is attempting to do, while thethe NIAID delineates the free services it provides through the Division of Microbiology and Infectious Diseases. This support should be of considerable interest to antimicrobial researchers, who may not be aware of its availability. The Community for Open Antimicrobial Resistance makes the case that it is essential to provide free early stage antibiotic screening support to foster fundamental research into new antibiotics. In a similar vein, the Wellcome Trust summarizes what it is doing to encourage antibiotic development, including its coordination of investment with other AMR agencies such as GARDP and the Combating Antibacterial Resistance Bacteria Accelerator (CARB-X). CARB-X itself has written a more substantial perspective, with a detailed breakdown of the three different funding rounds to date. CARB-X has vetted over 1100 applications (over 40% from companies with ≤10 employees), funding 60 projects to date from its investment pool of US$500 million. A joint viewpoint from authors working within the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) discusses the efforts of these agencies to reduce the barrier to antibiotic development by harmonizing regulatory requirements, while a venture capital opinion is offered by the only fund dedicated to antimicrobial resistance. Aleks Engel from The Novo REPAIR Fund explains their rationale for choosing to invest in this nonlucrative field. These institutional viewpoints are supplemented by two submissions from David Shlaes, a key opinion leader in antibiotics. The first focuses on the economic challenges of antibiotic development and contains suggestions on how to help small antibacterial biotech companies survive. The second gives a very powerful personal view of the value of antibiotics from the front lines of patient care based on his career as an infectious diseases physician. These overviews of the antibiotic field are followed by a collection of reviews, perspectives, and research manuscripts that nicely encapsulate the major strategies applied to antibiotic development, with contributions from both industrial and academic entities. A number of articles focus on improving traditional antibiotic classes, which has been the most successful strategy for producing new antibiotics over the past four decades. New β-lactamase inhibitor (BLI)/β-lactam combinations form a large component of the clinical antibiotic pipeline, and this prevalence is reflected in the number of research articles. Entasis, the antibiotic-focused company formed when Astra-Zeneca exited antibiotic research, provides two reports on their preclinical diazabicyclooctane (DBO) class BLI. ETX1317 is being developed as an orally available prodrug (ETX0282) to be administered with a cephalosporin prodrug, cefpodoxime proxetil. One article describes the in vitro activity of ETX1317 against a range of β-lactamase-expressing strains and 1875 Enterobacteriales isolates from UTI infections, with good activity against Class A, C, and D (but not B) carbapenemases. The second focuses on pharmacokinetic/pharmacodynamics, presenting both in vitro (hollow-fiber and chemostat) and in vivo (murine neutropenic thigh infection model) studies. From an academic perspective, the Schofield group at Oxford University characterize a broad spectrum BLI based on a thioether-substituted bicyclic boronate in Parkova et al. They show the potential for this class of inhibitors to provide activity against all three subclasses of metallo-β-lactamases. Tehrani et al. report that the known small molecule carboxylic acids nitrilotriacetic acid and N-(phosphonomethyl)iminodiacetic acid effectively inhibit the metallo-β-lactamases NDM-1 and VIM-2 by binding zinc, restoring the activity of meropenem in in vitro assays. Acting similarly to BLIs are other combination therapies that use a potentiator to restore the activity of an existing antibiotic against resistant bacteria. Researchers from McMaster University have worked with Spero Therapeutics to characterize the mechanism of action of their clinical potentiator SPR741, a polymyxin analog that potentiates several classes of antibiotics against resistant Gram-negative pathogens by disrupting the bacterial outer membrane. Ramirez et al. show that a bis(3-aminopropyl)glycine scaffold with three Arg residues capped with lipophilic tails could potentiate rifampicin and novobiocin to a similar extent as polymyxin B nonapeptide, at least in vitro. Ongwae et al. used polymyin B as a membrane-targeting scaffold to deliver a quaternary ammonium “warhead” onto the surface of bacterial pathogens, replacing the normal fatty acid tail with a lipophilic quaternary ammonium group: the adducts tended to be less potent than polymyxin B but retained the ability to potentiate rifamycin. In Hussein at al., Polymyxin B itself was found to work synergistically with sertraline, a selective serotonin reuptake inhibitor, against both polymyxin-susceptible and polymyxin-resistant isolates.In contrast, Dai et al. explore how nerve growth factor can work in combination with polymyxin to reduce its peripheral neurotoxicity. The use of potentiators is included in a review by Gray and Wenzel on multitarget approaches to treating resistant infections. The article has a broader scope than just potentiators and includes antibiotics that act on multiple targets, hybrid molecules designed to act on two targets, and antibiotic combination therapies. Rineh et al. provide an example of a conjugate that adds additional functionality to an existing traditional antibiotic. They modify a cephalosporin antibiotic scaffold with a prodrug moiety that releases nitric oxide as a biofilm dispersant. The best hybrid showed superior biofilm reduction compared to ceftazidime in in vitro testing and similar efficacy in an acute Pseudomonas aeruginosa murine lung infection model. The antibiotic discovery strategy of developing novel chemical scaffolds against a known target is exemplified in a review from Entasis that describes the development of Zoliflodacin, currently in Phase 3 clinical trials in partnership with GARD for drug resistant infections caused by Neisseria gonorrheae. Zoliflodacin is a new spiropyrimidinetrione scaffold that targets the bacterial type II topoisomerases but with a unique binding site (the GyrB subunit of DNA gyrase) and distinct mechanism of action compared to fluoroquinolones such as ciprofloxacin. In a similar vein, Spero Therapeutics offers a perspective on the development of GyrB inhibitors to treat infections caused by Mycobacterium tuberculosis and nontuberculous mycobacteria. Their examples start with the prototype aminocoumarin natural product inhibitor novabiocin and end with Spero’s benzimidazole urea clinical candidate SPR720, a prodrug originally developed by Vertex Pharmaceuticals. New chemical scaffolds acting on new bacterial targets are the “holy grail” of antibiotic discovery programs. Ma et al. from the Novartis Institutes for BioMedical Research present a structural analysis of their small molecule inhibitors of E. coli LpxD, an enzyme involved in lipid A biosynthesis in Gram-negative bacteria. This story highlights some of the pitfalls of drug discovery, as the actual inhibitors were found to be generated by in situ aromatization of the tested hexahydro-pyrazolo-quinolinone compounds. Post et al. describe their development of analogs of promalysin, a small-molecule natural product first isolated in 2011 that specifically inhibits P. aeruginosa. On the basis of its putative target of succinate dehydrogenase, they use computational modeling to identify a new binding cleft. Another potential new class of antibiotics is represented by pyrimidine analogs derived from 5-fluorouracil, described by Oe et al. These Gram-positive compounds target the same pathway as trimethoprim-sulfamethoxazole but probably act via inhibition of thymidylate synthetase. Notably, this paper employs RPMI medium with 10% fetal calf serum for the bacterial assays, rather than the standard Mueller Hinton (MH) broth. The RPMI mixture includes thymidine and serum proteins, which more closely approximates the environment where bacterial infections occur. This highlights a key question: should our quest for new antibiotics use screening conditions that are more reflective of the environs of infections? The search for inhibitors of new targets requires the development of target-specific assays, and Mitachi et al. contribute to this field with a fluorescence-based assay for the bacterial glycosyltransferase MurG, an enzyme involved in the conversion of lipid I to lipid II during peptidoglycan biosynthesis. Finally, an alternative strategy to treat resistant bacteria is taken by Vinagreiro et al., who describe the use of porphyrin photosensitizers to effectively kill multidrug-resistant clinical isolates and inactivate bacteria in biofilms. This antibacterial photodynamic inactivation approach obviously has practical limitations but could be useful for surface wound (skin, eye) or cavity (mouth, ear) infections. In closing, I would like to express my appreciation to all the authors and reviewers who have taken time from their busy schedules to contribute to this special issue. The articles in this ACS Infectious Diseases joint special issue are supplemented by additional articles in ACS Pharmacology & Translational Science. Hopefully, the collection will inspire new ideas and new researchers to contribute to the fight against antimicrobial resistance. Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author declares the following competing financial interest(s): M.A.T.B. has received funding from the Wellcome Trust, GARDP, and CARB-X, is using antimicrobial services provided by NIAID, and has previously engaged David Shlaes as a consultant. He is a cofounder of CO-ADD, which is collaborating with the Pew Trust on the SPARK initiative. He has additional research funding from both industry and government sources to develop novel antibiotics, is an inventor on antibiotic-related patents, and consults for antibiotic companies. He is a co-author on two articles mentioned in this editorial. 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抗生素特刊：抗生素发现与开发中的挑战与机遇。

本文是 抗生素类特刊。在过去的十年中，抗菌素耐药性（AMR）受到了越来越多的全球关注。临床渠道中缺乏抗生素是其商业发展受到不利的财政刺激的直接结果。正如当前的COVID-19危机所看到的那样，这导致了不稳定的情况，其中高抗性菌株的广泛出现可能威胁全球卫生系统的生存。尽管许多非抗生素替代抗菌方法显示出有趣的潜力，但很难预见它们将如何在可预见的将来取代对新抗生素的需求。这本关于抗生素的专刊集各种观点，观点，评论，和原始研究手稿，概述了抗生素发现和开发的当前状况。它是由十个相互关联的观点和来自许多对抗菌素耐药性感兴趣的世界领先机构和主要观点领袖的两个观点所扎根的。世界卫生组织的AMR部门和皮尤基金会（Pew Trust）均概述了抗生素开发面临的困难。WHO的观点总结了其有关临床前和临床抗菌药水管道的最新报告，前者显示145个个体机构正在开发252种抗菌药物，而后者则包括50种抗生素及其组合。皮尤基金会（Pew Trust）在尝试促进抗生素发现数据和知识共享方面分享了其进展，并讨论了如何更有效地针对抗生素发现工作。它敦促继续提供早期研究经费，并采取更加协调一致的行动，并提到全球抗生素研究与开发伙伴关系（GARDP）和美国过敏和传染病研究所（NIAID）为支持抗生素开发所做的努力。这两个组织也都提供了观点。GARDP概述了其成立的原因以及正在尝试做的事情，而NIAID则概述了它通过微生物学和传染病司提供的免费服务。抗菌研究人员可能对这种支持很感兴趣，他们可能不知道其可用性。开放抗菌素耐药性社区认为必须提供免费的早期抗生素筛查支持以促进对新抗生素的基础研究。同样，惠康基金会总结了鼓励抗生素开发的措施，包括与其他抗菌药物耐药机构（如GARDP和抗细菌耐药性细菌促进剂（CARB-X））进行投资协调。CARB-X本身写了一个更实质性的观点，详细介绍了迄今为止的三轮融资。CARB-X已经审核了1100多个应用程序（超过40％的员工人数少于10名的公司），迄今已从其5亿美元的投资池中资助了60个项目。来自美国食品药品监督管理局（FDA）的作者的共同观点，欧洲药品管理局（EMA）和日本药品和医疗器械局（PMDA）讨论了这些机构通过协调监管要求来减少抗生素开发障碍的努力，而唯一的风险投资意见是专门用于抗菌素耐药性。来自Novo REPAIR基金的Aleks Engel解释了他们选择在这一非好运领域投资的理由。这些制度性观点得到了抗生素主要观点领导者David Shlaes的两份意见书的补充。第一部分着重于抗生素开发的经济挑战，并包含有关如何帮助小型抗菌生物技术公司生存的建议。第二篇文章根据他作为传染病医生的职业，从患者护理的最前沿对抗生素的价值给出了非常有力的个人看法。在抗生素领域的这些概述之后，汇集了评论，观点和研究手稿，很好地概括了应用于抗生素开发的主要策略，并得到了工业界和学术界的贡献。许多文章集中于改进传统抗生素类别，这是过去四十年来生产新抗生素的最成功策略。新的β-内酰胺酶抑制剂（BLI）/β-内酰胺组合物构成临床抗生素产品线的重要组成部分，这种流行率在许多研究文章中得到了反映。Entasis，阿斯利康（Astra-Zeneca）退出抗生素研究时成立的以抗生素为重点的公司，就其临床前二氮杂双环辛烷（DBO）BLI类提供了两份报告。ETX1317正在开发为口服可用的前药（ETX0282），与头孢菌素前药头孢泊肟肟酯一起给药。一篇文章描述了ETX1317对一系列表达β-内酰胺酶的菌株和1875株来自UTI感染的肠杆菌的体外活性，对A，C和D类（而非B类）碳青霉烯酶具有良好的活性。第二个重点是药代动力学/药效学，介绍了体外（中空纤维和化学恒温器）和体内（鼠中性粒细胞减少大腿感染模型）研究。从学术的角度来看，牛津大学的Schofield研究小组在Parkova等人的著作中描述了一种基于硫醚取代的双环硼酸酯的广谱BLI。它们显示出这类抑制剂提供针对金属β-内酰胺酶的所有三个亚类的活性的潜力。Tehrani等。报告称，已知的小分子羧酸次氮基三乙酸和N-（膦酰基甲基）亚氨基二乙酸可通过结合锌有效抑制金属-β-内酰胺酶NDM-1和VIM-2，从而在体外恢复美罗培南的活性分析。与BLI相似的作用是使用增强剂恢复现有抗生素抗药性的活性的其他联合疗法。麦克马斯特大学的研究人员与Spero Therapeutics共同研究了其临床增效剂SPR741的作用机理，SPR741是一种多粘菌素类似物，可通过破坏细菌外膜来增强针对耐药革兰氏阴性病原体的多种抗生素。拉米雷斯等。表明具有三个Arg残基并被亲脂性尾巴封端的双（3-氨基丙基）甘氨酸支架至少在体外可以增强利福平和新生霉素的强度与多粘菌素B九肽相似。Ongwae等。使用多粘菌素B作为靶向膜的支架，将季铵“战斗部”递送到细菌病原体的表面，用亲脂性季铵基团代替了正常的脂肪酸尾巴：加合物的效力往往比多粘菌素B低，但保留了增强利福霉素的能力。在侯赛因等人的研究中，发现多粘菌素B本身与舍曲林（一种选择性的5-羟色胺再摄取抑制剂）对多粘菌素敏感和多粘菌素耐药菌分离株具有协同作用。探索神经生长因子如何与多粘菌素结合使用以减少其周围神经毒性。Gray和Wenzel在关于治疗耐药性感染的多靶点方法的评论中包括使用增效剂。该文章的范围不仅限于增强剂，还包括作用于多个靶标的抗生素，旨在作用于两个靶标的杂合分子以及抗生素联合疗法。Rineh等。提供了缀合物的实例，该缀合物为现有的传统抗生素增加了附加功能。他们用前药部分修饰头孢菌素抗生素支架，该前药部分释放一氧化氮作为生物膜分散剂。与头孢他啶相比，最好的杂种表现出更好的生物膜减少能力。他们用前药部分修饰头孢菌素抗生素支架，该前药部分释放一氧化氮作为生物膜分散剂。与头孢他啶相比，最好的杂种表现出更好的生物膜减少能力。他们用前药部分修饰头孢菌素抗生素支架，该前药部分释放一氧化氮作为生物膜分散剂。与头孢他啶相比，最好的杂种表现出更好的生物膜减少能力。急性铜绿假单胞菌小鼠肺部感染模型的体外测试和类似疗效。在Entasis的一篇综述中举例说明了开发针对已知靶标的新型化学支架的抗生素发现策略，该综述描述了Zoliflodacin的开发，目前正在与GARD进行3期临床试验，以治疗淋病奈瑟菌引起的耐药性感染。。Zoliflodacin是一种新型的螺旋嘧啶三酮支架，其靶向细菌II型拓扑异构酶，但具有独特的结合位点（DNA促旋酶的GyrB亚基），并且与环丙沙星（如环丙沙星）相比具有独特的作用机制。同样，Spero Therapeutics为GyrB抑制剂的开发提供了前景，该抑制剂可治疗结核分枝杆菌引起的感染和非结核分枝杆菌。他们的例子以氨基香豆素天然产物抑制剂新生物素的原型开始，以Spero的苯并咪唑脲临床候选药物SPR720（一种由Vertex Pharmaceuticals最初开发的前药）结束。作用于新细菌靶标的新化学支架是抗生素发现计划的“圣杯”。Ma等。诺华生物医学研究所的研究人员对他们的大肠杆菌LpxD的小分子抑制剂进行了结构分析，该酶是革兰氏阴性细菌中脂质A生物合成的一种酶。这个故事强调了药物发现的一些陷阱，因为发现了真正的抑制剂是原位产生的测试的六氢-吡唑并喹啉酮化合物的芳构化。邮政等。描述了他们开发promalysin类似物的过程，promalysin是一种小分子天然产物，于2011年首次分离，特异性抑制铜绿假单胞菌。根据其假定的琥珀酸脱氢酶靶标，他们使用计算模型来识别新的结合裂隙。另一种潜在的新型抗生素以Oe等人描述的衍生自5-氟尿嘧啶的嘧啶类似物为代表。这些革兰氏阳性化合物的靶向途径与甲氧苄氨嘧啶-磺胺甲基异恶唑相同，但可能通过抑制胸苷酸合成酶起作用。值得注意的是，本文采用的是含有10％胎牛血清的RPMI培养基，而不是标准的Mueller Hinton（MH）肉汤。RPMI混合物包含胸苷和血清蛋白，它们更接近细菌感染发生的环境。这突出了一个关键问题：我们对新抗生素的追求应该使用更能反映感染环境的筛选条件吗？寻找新靶标的抑制剂需要开发靶标特异性的检测方法，Mitachi等人。通过基于荧光的细菌糖基转移酶MurG分析为这一领域做出了贡献，MurG是一种在肽聚糖生物合成过程中参与脂质I转化为脂质II的酶。最后，Vinagreiro等人采取了另一种治疗耐药细菌的策略，他们描述了使用卟啉光敏剂有效杀死具有多重耐药性的临床分离株并使生物膜中的细菌失活。这种抗菌的光动力灭活方法显然具有实际的局限性，但可用于表面伤口（皮肤，眼睛）或腔（口，耳）感染。最后，在此，我要感谢所有从忙碌的工作中抽出时间为这一特殊问题做出贡献的作者和审稿人。本文中的文章ACS传染病联合特刊由ACS药理学和转化科学中的其他文章补充。希望该馆藏能够激发新的想法和新的研究人员，为抗微生物药物耐药性的斗争做出贡献。本社论中表达的观点只是作者的观点，不一定是ACS的观点。作者宣称以下竞争的财务利益：MATB已从惠康基金会（Wellcome Trust），GARDP和CARB-X获得资金，正在使用NIAID提供的抗菌服务，并曾聘请David Shlaes作为顾问。他是CO-ADD的共同创始人，该公司正与Pew Trust合作开展SPARK计划。他从工业界和政府那里获得了额外的研究经费，用于开发新型抗生素，是抗生素相关专利的发明者，并为抗生素公司提供咨询。他是本社论提到的两篇文章的合著者。