This article is part of the Antibiotic Alternatives special issue. There can be no doubt that antimicrobial resistance threatens the foundations of modern medicine. A recent report(1) examining the impact of drug-resistant infections on other areas of healthcare provides clear evidence of adverse effects on patients undergoing surgery and organ transplants, patients suffering from cancer, diabetes, HIV, immunodeficiency, liver and kidney disease, and physical trauma, and general populations of ICU patients and infants and children. The concluding sentence, “With drug-resistant infections increasingly undermining modern medicine, we must transform the global approach to stemming their rise and spread.”, highlights the need for innovative new approaches for treating infections beyond traditional antibiotics. Nonantibiotic antibacterial therapies encompass a wide range of different strategies, as outlined in a summary of the clinical pipeline of nontraditional approaches in 2016(2) and overviews of research strategies in 2019–2020.(3,4) The Pew Trust maintains a database for “Nontraditional Products for Bacterial Infections in Clinical Development” that is updated every 6 months.(5) Differences and similarities in the clinical development of traditional and nontraditional agents were recently outlined from a regulatory perspective.(6) Notably, funding agencies are beginning to respond to the need for alternative thinking, with, for example, a Defense Advanced Research Projects Agency (DARPA) funding call to develop novel strategies/modalities to effectively treat microbial infections using proteolysis targeting chimeras (PROTACs).(7) The 2019 funding rounds of the CARB-X antimicrobial initiative included one restricted to nontraditional approaches: “alternatives to antibiotics–including, for example, indirect-acting small molecule therapeutics, direct acting or indirect-acting large molecules, microbiome, phage, nucleic acid/antisense, and drug conjugates.”(8) This special issue provides a microcosm of many of these strategies. Indeed, the collection is anchored by a CARB-X authored Perspective that summarizes their current portfolio of nontraditional projects (DOI: 10.1021/acsinfecdis.1c00331). Another Perspective argues that governments must play a key role in supporting antimicrobial drug development, with a focus on the additional challenges for “nonantibiotic” therapeutics (DOI: 10.1021/acsinfecdis.0c00681). Anti-infective pundit David Shlaes provides a Viewpoint that highlights the balance needed between innovation and clinical utility (DOI: 10.1021/acsinfecdis.1c00227). The PROTAC approach is receiving significant attention as a general drug development strategy across multiple therapeutic areas, and a Review by Powell et al. examines how this might be applied to create antibacterial modalities (DOI: 10.1021/acsinfecdis.1c00203). The research articles in this issue fall into several themes. Approaches that leverage host defense mechanisms include the stimulation of the immune system by using monophosphoryl lipid A to enhance the treatment of invasive pneumonia (DOI: 10.1021/acsinfecdis.1c00176) and the repurposing of the antimalarial drug amodiaquine as a host-targeting therapy to treat anthrax, by blocking anthrax-toxin endocytosis (DOI: 10.1021/acsinfecdis.1c00190). The latter study is particularly significant as it provides compelling evidence for improved survival in mouse and rabbit models of anthrax infection, supporting the potential emergency use of an already approved drug for an indication where ethical human efficacy Phase 2 and 3 trials are not possible. Another paper that engages host responses found that noncytotoxic doses of silver nanoparticles coated with zinc oxide stimulated not only the proliferation and migration of human keratinocytes but also the production of antimicrobial peptides (DOI: 10.1021/acsinfecdis.0c00903). In terms of host response, Avery et al. show both human and bovine lactoferrin (an innate immune glycoprotein produced in high concentrations in human and bovine milk with known antibacterial properties) are effective at inhibiting Acinetobacter baumannii vegetative growth and biofilm formation at physiologically relevant concentrations, though the effectiveness varied depending on the anatomical origin of the clinical bacterial isolates tested (DOI: 10.1021/acsinfecdis.1c00087). Multiple papers examine the potential use of enzyme-based therapies. A bacteriophage endolysin was fused to a membrane-permeabilizing peptide to improve Gram-negative activity, creating an A. baumannii-targeting construct that was effective in a wax moth Galleria mellonella infection model (DOI: 10.1021/acsinfecdis.1c00222). Domain shuffling was used to create a chimeric Staphylococcus aureus endolysin that was effective in a systemic mouse model of infection (DOI: 10.1021/acsinfecdis.0c00812), while a Streptococcus pneumoniae endolysin was formulated in liposomes for sustained release, showing efficacy against both planktonic and biofilm S. pneumoniae (DOI: 10.1021/acsinfecdis.1c00108). Phage therapy, using the bacteriophages from which these lyins are derived, is also included in this issue. An E. coli bacteriophage was tested in combination with Lactobacillus probiotic strains as a treatment to control diarrhea in newborn calves (DOI: 10.1021/acsinfecdis.1c00010). Finally, a variety of potentiator/antivirulence strategies are described. A peptidomimetic linear peptide with minimal inherent antimicrobial activity effectively sensitized resistant Gram-negative bacteria to antibiotics such as rifampicin and macrolides, with demonstration of in vivo efficacy (DOI: 10.1021/acsinfecdis.1c00147). Pseudomonas biofilms have also been targeted with a biofilm-degrading enzyme, the glycoside hydrolase PslG, which was incorporated into lipid liquid crystal nanoparticles along with tobramycin. In this case, efficacy was evaluated in a nematode Caenorhabditis elegans infection model (DOI: 10.1021/acsinfecdis.1c00014). Another potentiator approach employed synthetic mimetics of siderophores, iron chelators used by bacteria to uptake essential iron. Gallium(II) complexes disrupted ion trafficking in A. baumannii, showing potent growth inhibition (DOI: 10.1021/acsinfecdis.1c00119). Hopefully, the span of articles contained in this issue will stimulate and inspire “out of the box” thinking for new approaches to combat antimicrobial resistance. Notably, a number of additional articles were submitted for consideration in this issue but were unable to proceed through the review process in time for inclusion. If accepted, they will be published in a regular issue but linked to this special issue—so please check back in the future! This article references 8 other publications.

中文翻译：

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抗生素替代品特刊

这篇文章是部分 抗生素替代品特刊。毫无疑问，抗微生物药物耐药性威胁着现代医学的基础。最近的一份报告 (1) 研究了耐药性感染对医疗保健其他领域的影响，明确证据表明对接受手术和器官移植的患者、患有癌症、糖尿病、艾滋病毒、免疫缺陷、肝肾疾病的患者以及身体创伤，以及 ICU 患者和婴儿和儿童的一般人群。最后一句话，“随着耐药性感染日益削弱现代医学，我们必须转变全球方法来阻止它们的兴起和蔓延。”，强调了在传统抗生素之外治疗感染的创新新方法的必要性。非抗生素抗菌疗法包含广泛的不同策略，如 2016 年 (2) 非传统方法临床管道摘要和 2019-2020 年研究策略概述中所述。 (3,4) 皮尤信托基金会维护一个数据库，用于“用于临床开发细菌感染的非传统产品”每 6 个月更新一次。(5) 最近从监管角度概述了传统和非传统药物临床开发的异同。(6) 值得注意的是，资助机构开始响应替代思维的需求，例如，国防高级研究计划局 (DARPA) 的资助呼吁，以开发使用靶向嵌合体 (PROTAC) 的蛋白水解有效治疗微生物感染的新策略/方式。(7) 2019 年 CARB-X 抗菌计划的资助轮次包括一项仅限于非传统方法的资助：“抗生素的替代品——包括，例如，间接作用的小分子疗法、直接作用或间接作用的大分子、微生物组、噬菌体、核酸/反义和药物偶联物。”(8) 本期特刊提供了一个缩影其中许多策略。事实上，该系列以 CARB-X 撰写的 Perspective 为基础，总结了他们当前的非传统项目组合（DOI：10.1021/acsinfecdis.1c00331）。另一种观点认为，政府必须在支持抗菌药物开发方面发挥关键作用，重点关注“非抗生素”疗法的额外挑战（DOI：10.1021/acsinfecdis.0c00681）。抗感染专家 David Shlaes 提出了一个观点，强调了创新和临床效用之间所需的平衡（DOI：10.1021/acsinfecdis.1c00227）。PROTAC 方法作为跨多个治疗领域的一般药物开发策略受到了极大的关注，Powell 等人的评论。研究如何将其应用于创建抗菌方式（DOI：10.1021/acsinfecdis.1c00203）。本期的研究文章分为几个主题。利用宿主防御机制的方法包括通过使用单磷酰脂质 A 刺激免疫系统以增强侵袭性肺炎的治疗 (DOI: 10.1021/acsinfecdis.1c00176) 以及重新利用抗疟药阿莫地喹作为宿主靶向治疗来治疗炭疽，通过阻断炭疽毒素内吞作用（D​​OI：10.1021/acsinfecdis.1c00190）。后一项研究特别重要，因为它为提高炭疽感染小鼠和兔模型的存活率提供了令人信服的证据，支持了一种已获批准的药物的潜在紧急使用，用于无法进行合乎道德的人体功效 2 和 3 期试验的适应症。另一篇涉及宿主反应的论文发现，非细胞毒性剂量的涂有氧化锌的银纳米颗粒不仅刺激了人类角质形成细胞的增殖和迁移，还刺激了抗菌肽的产生（DOI：10.1021/acsinfecdis.0c00903）。在主机响应方面，Avery 等人。表明人和牛乳铁蛋白（一种在人和牛乳中以高浓度产生的具有已知抗菌特性的先天免疫糖蛋白）可有效抑制鲍曼不动杆菌在生理相关浓度下的营养生长和生物膜形成，但有效性因所测试的临床细菌分离株的解剖来源而异（DOI：10.1021/acsinfecdis.1c00087）。多篇论文研究了基于酶的疗法的潜在用途。噬菌体细胞内溶素与膜通透肽融合，以提高革兰氏阴性活性，创建鲍曼不动杆菌靶向构建体，该构建体在蜡蛾Galleria mellonella感染模型中有效（DOI：10.1021/acsinfecdis.1c00222）。域改组用于创建嵌合金黄色葡萄球菌内溶素在系统性小鼠感染模型中有效（DOI：10.1021/acsinfecdis.0c00812），而肺炎链球菌内溶素配制在脂质体中用于持续释放，显示出对浮游和生物膜肺炎链球菌的功效（DOI：10.1021/acsinfecdisac） .1c00108）。本期还包括噬菌体疗法，使用这些赖氨酸来源的噬菌体。一种大肠杆菌噬菌体与乳酸杆菌结合进行了测试益生菌菌株作为控制新生犊牛腹泻的治疗方法（DOI：10.1021/acsinfecdis.1c00010）。最后，描述了各种增强剂/抗毒力策略。一种具有最小固有抗菌活性的拟肽线性肽有效地使耐药革兰氏阴性菌对抗生素如利福平和大环内酯敏感，并证明了体内功效（DOI：10.1021/acsinfecdis.1c00147）。假单胞菌生物膜也被靶向生物膜降解酶，即糖苷水解酶 PslG，该酶与妥布霉素一起掺入脂质液晶纳米颗粒中。在这种情况下，对线虫秀丽隐杆线虫的疗效进行了评估感染模型（DOI：10.1021/acsinfecdis.1c00014）。另一种增强剂方法采用铁载体的合成模拟物，即细菌用来吸收必需铁的铁螯合剂。镓 (II) 复合物破坏了鲍曼不动杆菌中的离子运输，显示出有效的生长抑制作用 (DOI: 10.1021/acsinfecdis.1c00119)。希望本期所载文章的范围能够激发和激发“开箱即用”的思维，以寻找对抗抗菌素耐药性的新方法。值得注意的是，本期还提交了一些额外的文章供审议，但未能及时通过审查过程以供纳入。如果被接受，它们将在常规问题上发表，但与本期特刊相关联——所以请以后再来看看！本文引用了 8 篇其他出版物。