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
基本信息
- 批准号:MR/Y033809/1
- 负责人:
- 金额:$ 23.35万
- 依托单位:
- 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:
- 关键词:
项目摘要
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.
多药耐药(MDR)病原体的增加已成为全球关注的问题。据估计,2019年全球有495万人死于耐药细菌感染。其中,127万例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)报告说,耐药性细菌感染导致33,000人死亡(欧洲经济区的数据)。同样,在美国,CDC估计每年发生超过280万起耐药性感染,导致超过35,000人死亡。世卫组织和疾病预防控制中心已确定革兰氏阴性病原体,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)的碳青霉烯耐药菌株,作为紧急或严重的威胁。关于与耐药性相关的死亡人数,六种主要病原体(E。coli、S.金黄色葡萄球菌K. pneumoniae、肺炎链球菌(Streptococcus pneumoniae)、A.鲍曼不动杆菌和铜绿假单胞菌)导致2019年约929,000例AMR所致死亡。特别是,2015年在欧盟和欧洲经济区,耐粘菌素、碳青霉烯类或多重耐药铜绿假单胞菌对耐药细菌感染导致的死亡和残疾调整生命年的影响最大。因此,这些铜绿假单胞菌引起的感染的治疗是该领域明显未满足的医疗需求。在这方面,抗微生物肽,特别是那些环状的、非核糖体生物合成的(或核糖体合成的和后修饰的)抗微生物肽提供了作为潜在药物开发的机会。在这类药物中,我们发现了众所周知的临床使用的药物,如达托霉素和多粘菌素(多粘菌素B和多粘菌素E/粘菌素,以多粘菌素E甲磺酸盐的前药形式使用)或新的化合物,如达柔菌素或teixobactin。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)引起的感染的最后治疗选择。多粘菌素是最后使用的抗生素时,没有其他治疗选择,由于其肾毒性和神经毒性。因此,没有这种副作用的新型多粘菌素的可用性对于治疗由多药耐药(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,包括临床使用或临床开发阶段的环肽抗生素,以减少其肾毒性。设计的基本原理包括维持抗生素的整体结构以保持抗菌活性,而肽骨架内化学工具的存在将促进抗生素最终在肾脏中积累时通过解毒酶的初始代谢。该项目遵循一个概念验证方案,涉及制备模型化合物所需的化学过程,评估活性和低毒性的体外和体内试验,以及估计治疗窗口。最后,还提出了在膜水平上验证设计假设和作用机制的试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Timothy Walsh其他文献
Assessing decision boundaries under uncertainty
评估不确定性下的决策边界
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:3.9
- 作者:
Wilkins Aquino;Jacob Desmond;Michael Eldred;Andrew Kurzawski;Cameron McCormick;Clay Sanders;Chandler Smith;Timothy Walsh - 通讯作者:
Timothy Walsh
Neural and Behavioral Mechanisms of Food Decision Making Across a Spectrum of Restrictive Eating
- DOI:
10.1016/j.biopsych.2020.02.078 - 发表时间:
2020-05-01 - 期刊:
- 影响因子:
- 作者:
Karin Foerde;Janet Schebendach;Nathaniel Daw;Timothy Walsh;Daphna Shohamy;Joanna Steinglass - 通讯作者:
Joanna Steinglass
Neocortical neuronal morphology in the Siberian Tiger (Panthera tigris altaica) and the clouded leopard (Neofelis nebulosa)
西伯利亚虎(Panthera tigris altaica)和云豹(Neofelis nebulosa)的新皮质神经元形态
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Cameron B. Johnson;M. Schall;Mackenzie E. Tennison;Madeleine E Garcia;N. B. Shea;M. Raghanti;A. Lewandowski;Mads F Bertelsen;Leona C. Waller;Timothy Walsh;John F. Roberts;P. Hof;C. Sherwood;P. Manger;B. Jacobs - 通讯作者:
B. Jacobs
The Triple Combination of Meropenem, Avibactam, and a Metallo-β-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different β-Lactamase Producers
美罗培南、阿维巴坦和金属-β-内酰胺酶抑制剂的三重组合可优化针对不同 β-内酰胺酶生产者的抗菌覆盖范围
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:12.8
- 作者:
Zhuoren Ling;Alistair James Macdonald Farley;Aditya Lankapalli;Yanfang Zhang;Shonnette Premchand;Kate Cook;Andrei Baran;Charlotte Gray;Claudia Orbegozo Rubio;Edgars Suna;Jordan Mathias;J. Brem;Kirsty Sands;Maria Nieto;Maria Mykolaivna Trush;Nadira Naznin Rakhi;Willames Martins;Yuqing Zhou;Christopher Joseph Schofield;Timothy Walsh - 通讯作者:
Timothy Walsh
Process Improvement: Use of UV-C for Healthcare Cell Phone Disinfection.
工艺改进:使用 UV-C 进行医疗保健手机消毒。
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:4.9
- 作者:
Jacqueline Christie;Timothy Walsh;Christopher Lee;P. Stefanacci - 通讯作者:
P. Stefanacci
Timothy Walsh的其他文献
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{{ truncateString('Timothy Walsh', 18)}}的其他基金
Determining the clinical and environmental impact, burden and cost of Extensively Drug Resistant Enterobacteriaceae in China (DETER-XDRE-CHINA-HUB)
确定中国广泛耐药肠杆菌科细菌的临床和环境影响、负担和成本 (DETER-XDRE-CHINA-HUB)
- 批准号:
MR/S013768/2 - 财政年份:2020
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
Determining the clinical and environmental impact, burden and cost of Extensively Drug Resistant Enterobacteriaceae in China (DETER-XDRE-CHINA-HUB)
确定中国广泛耐药肠杆菌科细菌的临床和环境影响、负担和成本 (DETER-XDRE-CHINA-HUB)
- 批准号:
MR/S013768/1 - 财政年份:2019
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
China/UK/Thailand Program on Poultry Biosafety for Salmonella, E. coli and Campylobacter (CUT-SEC)
中国/英国/泰国家禽沙门氏菌、大肠杆菌和弯曲杆菌生物安全项目 (CUT-SEC)
- 批准号:
BB/R012776/1 - 财政年份:2018
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
Determining the clinical and environmental impact, burden and cost of extensively drug resistant Enterobacteriaceae in China (DETER-XDRE-CHINA)
确定中国广泛耐药肠杆菌科细菌的临床和环境影响、负担和成本 (DETER-XDRE-CHINA)
- 批准号:
MR/P007295/1 - 财政年份:2016
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
Assessing the situation of AMR of bacteria in Vietnam, determining genomic characteristics and associated factors of common AMR-bacteria in Vietnam
评估越南细菌的AMR状况,确定越南常见AMR细菌的基因组特征和相关因素
- 批准号:
MR/N028317/1 - 财政年份:2016
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
Combatting the threat of carbapenem resistance in Gram-negative bacterial pathogens
对抗革兰氏阴性细菌病原体的碳青霉烯类耐药性威胁
- 批准号:
G1100135/1 - 财政年份:2011
- 资助金额:
$ 23.35万 - 项目类别:
Research Grant
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Keratin-dependent regulation of progenitor keratinocyte identity and commitment to differentiation
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