This article is part of the Antibiotics special issue. Anti-infectives have saved countless lives and decreased mortality worldwide since the discovery of penicillin in 1928. Considered as therapeutic “magic-bullets”, antibiotics have revolutionized modern medicine and made many complicated medical procedures possible. The 1960s and 1970s were a boom time for antibiotic discovery and a large number of different compound classes were discovered and approved for clinical use to treat infections which were once fatal. Unfortunately, over the last four decades, resistance to the commonly used antibiotics has been rapidly increasing. Even worse, the traditional business model of antibiotic research and development has failed to attract investment from the pharmaceutical industry due to growing costs associated with development, increasing regulatory hurdles, and poor financial returns compared to life-style drugs.(1) Since, the call of “Bad Bugs, No Drug” by the Infectious Diseases Society of America (IDSA) in 2003, the Centres for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have highlighted the urgency for discovery and development of novel antibiotics for the life-threatening infections caused by a number of bacterial “superbugs”. Encouragingly, several nonprofit partnerships have been established over the past few years to accelerate the development of innovative antibacterial therapeutics and rapid diagnostics. Notable examples include CARB-X, the Biomedical Advanced Research and Development Authority (BARDA, USA), the National Institute of Allergy and Infectious Diseases (NIAID, part of the National Institutes of Health [NIH]), the Wellcome Trust (UK), the Bill & Melinda Gates Foundation, German Federal Ministry of Education and Research, and the UK Global Antimicrobial Resistance Innovation Fund (GAMRIF). These efforts appear to have paid dividends, as there has been a steadily increasing number of new antibiotic approvals since 2013, including several with novel mechanisms of action.(2) Notwithstanding the development of new compounds, it is also crucial that clinical practices serve to minimize the emergence of resistance to existing off-the-shelf antibiotics and implement proper stewardship and scientifically based dosage recommendations, thereby prolonging the clinical utility as long as possible. This Special Issue, part of a joint antibiotics Special Issue with ACS Infectious Diseases, on antibiotic development presents six examples from the rapid point-of-care diagnostics in respiratory tract infections, optimization of antibiotic dosing in patients using pharmacometrics, development of novel combination therapy via repurposing, and understanding the mode of action of antibiotics, to the development of novel antibiotics. Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) have a significant mortality globally. A mini-review from a United Kingdom perspective highlights the significant potential of rapid molecular diagnostics in improving clinical practice and antibiotic stewardship.(3) In particular, rapid confirmation of bacterial infections and timely identification of the causative pathogens are crucial for providing optimal treatment. Clearly, major challenges are raised in maintaining quality control and infection control input and the reliability of rapid molecular diagnostic tests. Without new antibiotics, optimizing the use of currently available antibiotics is crucial in treating multidrug-resistant bacterial pathogens. Over the last four decades, pharmacokinetic/pharmacodynamic (PK/PD) modeling has played a major role in optimizing the dosage regimens of antibiotics and minimizing emergence of resistance. Landersdorfer and colleagues developed a physiologically based population pharmacokinetic model for ciprofloxacin in bone in patients undergoing orthopedic surgery.(4) Although ciprofloxacin has been used in the clinic for more than three decades, the time-course of ciprofloxacin in bone has never been characterized in patients using population PK modeling. With this newly developed model and Monte Carlo simulations, probabilities of target attainment (PTA) analysis revealed that the currently approved maximum daily dose of ciprofloxacin may be suboptimal for all wild-type Staphylococcus aureus isolates with MICs up to the susceptible breakpoint (1 mg/L). This study shows the importance of PK/PD modeling in optimizing antibiotic use in the clinic. Another key approach to minimize antibiotic resistance is to develop novel combination therapy. Rafah et al. explored the mechanism of a potential synergistic combination of a last-line class of antibiotics polymyxins with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator against Pseudomonas aeruginosa.(5) Untargeted metabolomics results revealed that polymyxin killing is enhanced by ivacaftor mainly via the inhibition of cell envelope biogenesis and perturbations in the central carbohydrate metabolic network. This study indicates the potential of repurposing nonantibiotic drugs via synergistic combinations with currently available antibiotics; clearly, optimal PK/PD of both drugs at the infection site must be considered in order to achieve satisfactory efficacy. Drs Baral and Mozafari reviewed recent literature on the mechanisms of antibiotic resistance and the current antibiotic discovery and development pipeline.(6) Several key approaches on the development of novel antimicrobial therapeutics were discussed, including modifications of the chemical scaffolds of “old” antibiotics, efflux pump inhibitors, and the discovery of novel chemical scaffolds from marine natural products. To facilitate the discovery of novel oxazolidone antibiotics, Wright and colleagues employed cryo-electron microscopy to investigate the differences in the binding of several functionally different oxazolidinones to the peptidyl transferase center (PTC) of the 50S ribosomal subunit from Staphylococcus aureus.(7) The ribosome–antibiotic complexes resolved at a resolution of approximately 3 Å elucidated the structure–activity relationship of oxazolidone antibiotics, which will facilitate the design of new-generation oxazolidinones. Antimicrobial peptides play an important role in the innate immune system in nearly all multicellular organisms and usually have a broad spectrum against bacteria, fungi, and viruses.(8) Among them, ribosomally synthesized antimicrobial peptides in bacteria have diverse structures and are believed to have different mechanisms of antibacterial activity from current antibiotics. Fields et al. designed a library of linear peptides from a circular bacteriocin and demonstrated that the pore-formation in bacterial membranes by bacteriocin can be tuned by selectively substituting certain amino acids.(9) This study shows that engineering amino acid substitutions in reductive linear variants of natural bacteriocins may lead to the discovery of novel antimicrobial peptides against bacterial “superbugs”. In summary, innovative approaches are required in the development of novel therapeutics to treat multidrug-resistant bacterial infections. This Special Issue on antibiotics highlights how novel diagnostic tools and mechanistic understanding of drug action can optimize the use of current antibiotics and facilitate the discovery of novel antibacterial therapies. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. This article references 9 other publications.

中文翻译：

---

针对抗生素耐药性：从诊断到新型抗生素。


本文是该文章的一部分抗生素专刊。自 1928 年发现青霉素以来，抗感染药物在全球范围内挽救了无数生命并降低了死亡率。抗生素被视为治疗“灵丹妙药”，彻底改变了现代医学，使许多复杂的医疗程序成为可能。 20 世纪 60 年代和 1970 年代是抗生素发现的繁荣时期，大量不同的化合物类别被发现并被批准用于临床治疗曾经致命的感染。不幸的是，在过去四十年中，对常用抗生素的耐药性迅速增加。更糟糕的是，与生活方式药物相比，抗生素研发的传统商业模式由于开发成本不断增加、监管障碍增加以及财务回报不佳而未能吸引制药行业的投资。(1) 2003 年，美国传染病学会 (IDSA) 发出“没有坏虫，就没有药物”的号召，美国疾病控制与预防中心 (CDC) 和世界卫生组织 (WHO) 强调了发现和开发新型药物的紧迫性。抗生素用于治疗由许多细菌“超级细菌”引起的危及生命的感染。令人鼓舞的是，过去几年建立了一些非营利合作伙伴关系，以加速创新抗菌疗法和快速诊断的开发。 著名的例子包括 CARB-X、生物医学高级研究和开发局（BARDA，美国）、国家过敏和传染病研究所（NIAID，隶属于美国国立卫生研究院 [NIH]）、Wellcome Trust（英国）、比尔及梅琳达·盖茨基金会、德国联邦教育和研究部以及英国全球抗菌素耐药性创新基金 (GAMRIF)。这些努尽量减少对现有现成抗生素产生耐药性的情况，并实施适当的管理和基于科学的剂量建议，从而尽可能延长临床效用。本特刊是ACS 传染病联合抗生素特刊的一部分，关于抗生素开发，介绍了六个例子，包括呼吸道感染的快速护理点诊断、使用药理学优化患者抗生素剂量、开发新型联合疗法通过重新利用和了解抗生素的作用方式，来开发新型抗生素。医院获得性肺炎（HAP）和呼吸机相关性肺炎（VAP）在全球范围内死亡率很高。英国角度的小型审查强调了快速分子诊断在改善临床实践和抗生素管理方面的巨大潜力。(3) 特别是，快速确认细菌感染并及时识别致病病原体对于提供最佳治疗至关重要。显然，在维持质量控制和感染控制输入以及快速分子诊断测试的可靠性方面提出了重大挑战。如果没有新的抗生素，优化现有抗生素的使用对于治疗多重耐药细菌病原体至关重要。在过去的四十年中，药代动力学/药效学 (PK/PD) 模型在优化抗生素剂量方案和最大限度减少耐药性出现方面发挥了重要作用。 Landersdorfer 及其同事开发了一种基于生理学的环丙沙星在骨科手术患者骨中的群体药代动力学模型。(4) 尽管环丙沙星已在临床中使用了三十多年，但环丙沙星在骨中的时程从未被描述过。使用群体 PK 模型的患者。通过这个新开发的模型和蒙特卡罗模拟，目标达到概率 (PTA) 分析显示，目前批准的环丙沙星最大每日剂量对于所有 MIC 高达易感断点（1 mg/ L）。这项研究显示了 PK/PD 模型在优化临床抗生素使用方面的重要性。减少抗生素耐药性的另一个关键方法是开发新型联合疗法。拉法等人。探索了最后一类抗生素多粘菌素与囊性纤维化跨膜电导调节剂（CFTR）增强剂对抗铜绿假单胞菌的潜在协同作用机制。(5)非靶向代谢组学结果表明，ivacaftor 主要通过抑制细胞包膜生物发生和扰动中央碳水化合物代谢网络来增强多粘菌素杀伤作用。这项研究表明，通过与现有抗生素的协同组合，可以重新利用非抗生素药物；显然，为了达到满意的疗效，必须考虑两种药物在感染部位的最佳 PK/PD。 Baral 和 Mozafari 博士回顾了有关抗生素耐药性机制以及当前抗生素发现和开发管道的最新文献。(6) 讨论了开发新型抗菌疗法的几个关键方法，包括修改“旧”抗生素的化学支架，外排泵抑制剂，以及从海洋天然产物中发现新型化学支架。为了促进新型恶唑烷酮抗生素的发现，Wright 及其同事采用冷冻电子显微镜来研究几种功能不同的恶唑烷酮与金黄色葡萄球菌50S 核糖体亚基的肽基转移酶中心 (PTC) 结合的差异。(7)以约 3 Å 的分辨率解析核糖体-抗生素复合物，阐明了恶唑烷酮抗生素的结构-活性关系，这将有助于新一代恶唑烷酮的设计。抗菌肽在几乎所有多细胞生物的先天免疫系统中发挥着重要作用，通常具有广谱的抗细菌、真菌和病毒作用。(8)其中，细菌中核糖体合成的抗菌肽具有不同的结构，被认为具有与现有抗生素不同的抗菌活性机制。菲尔兹等人。设计了一个来自环状细菌素的线性肽库，并证明细菌素在细菌膜中的孔形成可以通过选择性取代某些氨基酸来调节。(9) 这项研究表明，在天然细菌素的还原性线性变体中进行氨基酸取代工程可能会导致发现针对细菌“超级细菌”的新型抗菌肽。总之，开发治疗多重耐药细菌感染的新疗法需要创新方法。本期关于抗生素的特刊强调了新型诊断工具和对药物作用机制的理解如何优化现有抗生素的使用并促进新型抗菌疗法的发现。本社论中表达的观点仅代表作者的观点，并不一定代表 ACS 的观点。本文参考了其他 9 篇出版物。