The disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin

二硫键作为环肽抗生素的化学工具：工程化二硫多粘菌素和 murepavadin

• 批准号: MR/Y033809/1
• 负责人: Timothy Walsh
• 金额: $ 23.35万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY033809%2F1
• 关键词: disulfide; bond; chemical; tool; cyclic

The increase of multidrug-resistant (MDR) pathogens has become a matter of global concern. It has been recently estimated that 4.95 million people died worldwide due to drug-resistant bacterial infections in 2019. Of those, 1.27 million deaths were directly attributed to antimicrobial resistance (AMR). In Europe, the European Centre for Disease Prevention and Control (ECDC) has reported that antibiotic-resistant bacterial infections caused 33,000 deaths (data for the European Economic Area). Similarly, in the US, the CDC estimates that more than 2.8 million antibiotic-resistant infections take place annually with more than 35,000 dead people as a consequence. The WHO and CDC have identified Gram-negative pathogens such as carbapenem-resistant strains of Acinetobacter baumannii, Enterobacteriaceae (which including Escherichia coli and Klebsiella pneumoniae), and Pseudomonas aeruginosa (also multi-drug resistant strains) as urgent or serious threats. Regarding the number of deaths associated with resistance, six leading pathogens (E. coli, S. aureus, K. pneumoniae, Streptococcus pneumoniae, A. baumannii, and P. aeruginosa) were responsible for ca 929,000 deaths attributable to AMR in 2019.In particular, colistin-resistant, carbapenem-resistant, or multidrug-resistant P. aeruginosa shows some of the highest impact related to deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015. Hence, the treatment of these P. aeruginosa caused infections is a clear unmet medical need in the field. In this regards, antimicrobial peptides, particularly those that are cyclic, non-ribosomally biosynthesized (or ribosomally synthesized and post-translationally modified) offer an opportunity to be explored as potential drugs. In this class we find well-known clinically-used drugs such as daptomycin and polymyxins (polymyxin B and polymyxin E/colistin, used in the prodrug form colistimethate) or novel compounds such as darobactin or teixobactin. Daptomycin is mostly indicated to treat Gram-positive Staphylococcus aureus caused infections, whereas polymyxins have become a last resort therapeutic option to treat multi-drug resistant (MDR) Gram-negative bacteria (GNB) caused infections. Polymyxins are used as last resort antibiotics when no other therapeutic option is available due to their nephrotoxicity and neurotoxicity. Hence, the availability of novel polymyxins devoid of such adverse effects would be a great advance for the treatment of infections caused by multi-drug resistant (MDR) Gram-negative bacteria. The project presents an innovative chemical tool to be applied to known cyclic peptide antibiotics, including those in clinical use or in a clinical development phase, to reduce their nephrotoxicity. The rationale of the design consists of maintaining the overall structure of the antibiotic to preserve the antibacterial activity while the presence of the chemical tool within the peptide backbone would facilitate the initial metabolization by detoxifying enzymes upon eventual accumulation of the antibiotic in the kidney. The project follows a proof-of-concept scheme involving the necessary chemistry to prepare the model compounds, the in vitro and in vivo assays to assess activity and low toxicity, and estimation the therapeutic window. Finally, tests to prove the design hypothesis and the mechanism of action at the membrane level are also proposed.

多重耐药（MDR）病原体的增加已成为全球关注的问题。最近估计，2019年全球有495万人因耐药细菌感染死亡。其中，127万人的死亡直接归因于抗菌素耐药性（AMR）。在欧洲，欧洲疾病预防和控制中心 (ECDC) 报告称，抗生素耐药性细菌感染导致 33,000 人死亡（欧洲经济区数据）。同样，在美国，疾病预防控制中心 (CDC) 估计，每年发生超过 280 万例抗生素耐药性感染，导致超过 35,000 人死亡。世界卫生组织和疾病预防控制中心已将革兰氏阴性病原体，如鲍曼不动杆菌、肠杆菌科（包括大肠杆菌和肺炎克雷伯菌）和铜绿假单胞菌（也是多重耐药菌株）的碳青霉烯类耐药菌株确定为紧急或严重威胁。关于与耐药性相关的死亡人数，2019 年，六种主要病原体（大肠杆菌、金黄色葡萄球菌、肺炎克雷伯菌、肺炎链球菌、鲍曼不动杆菌和铜绿假单胞菌）导致约 929,000 人因耐药性死亡。特别是，耐粘菌素、耐碳青霉烯类或多药耐药的铜绿假单胞菌显示出一些与相关影响最高的细菌。 2015 年欧盟和欧洲经济区因抗生素耐药细菌感染导致的死亡和伤残调整生命年。因此，治疗这些铜绿假单胞菌引起的感染显然是该领域未得到满足的医疗需求。在这方面，抗菌肽，特别是那些环状的、非核糖体生物合成的（或核糖体合成的和翻译后修饰的）提供了作为潜在药物进行探索的机会。在这一类中，我们发现了众所周知的临床使用药物，例如达托霉素和多粘菌素（多粘菌素 B 和多粘菌素 E/粘菌素，以前药形式粘菌素使用）或新型化合物，例如达罗巴汀或替克巴汀。达托霉素主要用于治疗革兰氏阳性金黄色葡萄球菌引起的感染，而多粘菌素已成为治疗多重耐药（MDR）革兰氏阴性菌（GNB）引起的感染的最后手段。由于多粘菌素的肾毒性和神经毒性，当没有其他治疗选择时，多粘菌素被用作最后的抗生素。因此，没有此类副作用的新型多粘菌素的出现对于治疗多重耐药（MDR）革兰氏阴性菌引起的感染将是一个巨大的进步。该项目提出了一种创新的化学工具，可应用于已知的环肽抗生素，包括那些处于临床使用或处于临床开发阶段的抗生素，以减少其肾毒性。该设计的基本原理包括维持抗生素的整体结构以保留抗菌活性，同时肽主链内化学工具的存在将通过抗生素最终在肾脏中积累时通过解毒酶促进初始代谢。该项目遵循概念验证方案，涉及制备模型化合物所需的化学反应、评估活性和低毒性的体外和体内测定以及估计治疗窗。最后，还提出了测试来证明设计假设和膜水平的作用机制。