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.

多药（MDR）病原体的增加已成为全球关注的问题。最近估计，由于2019年耐药细菌感染，全世界有495万人死亡。在这些细菌感染中，有127万人死亡直接归因于抗菌耐药性（AMR）。在欧洲，欧洲疾病预防与控制中心（ECDC）报道说，抗生素耐药的细菌感染造成33,000人死亡（欧洲经济领域的数据）。同样，在美国，疾病预防控制中心估计，每年有超过280万种抗生素耐药性感染发生在每年发生的35,000多人。 WHO和CDC已经鉴定出革兰氏阴性病原体，例如碳酸杆菌的碳青霉菌菌株Baumannii，肠杆菌科（包括大肠杆菌和Klebsiella pneumoniae），以及Pseudomonaseudomonasecudomonasequudomonasequudomonasearuginosa（也是多种驱动力的抗抗抗毒剂）或严重的抗强度抗性或严重的抗强度抗性。 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表明，与2015年欧盟抗生素耐药细菌的感染和欧洲经济区有关的死亡和残疾调整的终身年份的影响最大。因此，这些铜绿假单胞菌引起的感染的治疗是该领域的明显未满足的医疗需求。在这方面，抗菌肽，尤其是那些循环，非核糖体生物合成（或核糖体合成和翻译后修饰）的抗菌肽提供了一个机会，可以作为潜在药物进行探索。在此课程中，我们发现临床中著名的药物，例如daptomycin和polyxin（Polyxin b和多粘染素E/colistin），用于前药形成菌根）或新型化合物，例如Darobactin或Teixobactin。二霉素大多被指出可以治疗金黄色葡萄球菌引起的革兰氏葡萄球菌，而多粘霉素已成为治疗多药耐药（MDR）革兰氏阴性细菌（GNB）的最后度假胜地治疗选择。当由于其肾毒性和神经毒性而没有其他治疗选择时，多淋及素被用作最后度假抗生素。因此，没有这种不良反应的新型多氧化物的可利用性对于治疗由耐多药（MDR）革兰氏阴性细菌引起的感染是一个很好的进步。该项目提出了一种创新的化学工具，可应用于已知的循环肽抗生素，包括临床使用或临床发育阶段的抗生素，以降低其肾毒性。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，而肽骨架内化学工具的存在将促进抗肾脏中抗生素的最终积累来促进酶的初始代谢。该项目遵循概念验证方案，该方案涉及必要的化学反应，以准备模型化合物，体外和体内测定法，以评估活性和低毒性，并估计治疗窗口。最后，还提出了证明设计假设和膜水平上的作用机理的测试。