Extending bicyclomycin treatment of multi-drug resistant Gram-negative pathogens

延长双环霉素对多重耐药革兰氏阴性病原体的治疗

• 批准号: MR/P007570/1
• 负责人: Andrew Truman
• 金额: $ 62.53万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP007570%2F1
• 关键词: Extending; bicyclomycin; treatment; multi; drug

Antibiotics have saved millions of lives from infectious diseases and are arguably the greatest medical discovery of the 20th century. Unfortunately, one of the biggest threats to public health in the 21st century is the rise of multi-drug resistant bacterial infections. This rise has been caused by the improper use of antibiotics in medicine and agriculture combined with a shortage in the discovery of new types of antibiotics. This has prompted the World Health Organisation to warn that "with a dearth of new antibiotics coming to market, the need for action to avert a developing global crisis in health care is increasingly urgent", and the UK's Chief Medical Officer, Prof. Dame Sally Davies, to declare that "we are also not developing new drugs fast enough". This is a global problem that requires global action, particularly for the treatment of multi-drug resistant Gram-negative bacterial infections. Gram-negative bacteria are naturally resistant to many antibiotics used clinically, and have evolved to be resistant towards most other antibiotics following years of treatment with those medicines. There are various approaches to tackle this growing problem, including re-purposing "old" antibiotics. These are drugs that were thoroughly tested for efficacy and safety in human clinical trials, but were not then widely used for a variety of reasons. For example, better broad-spectrum alternatives may have been available at the time. The rise of multi-drug resistance means that these molecules may now be very useful, especially because their lack of clinical use means that there has not been an opportunity for resistance to develop in disease-causing bacteria. Additionally, new experiments can sometimes reveal antibacterial activities that were not identified in earlier research. This is the case for bicyclomycin, an old antibiotic that had previously been shown to have moderate bacteriostatic activity towards Gram-negative bacteria. "Bacteriostatic" means that the antibiotic stops bacterial growth, but does not actively kill the bacteria, which can lead to the persistence of an infection. Excitingly, recent work has shown that bicyclomycin can actually kill bacteria ("bactericidal") when it is used alongside another bacteriostatic antibiotic. This unexpected activity makes bicyclomycin a highly promising antibiotic for the treatment of Gram-negative bacterial infections when used in combination with another drug. Therefore, we propose to carry out further work to determine whether bicyclomycin can be widely used in the clinic. This will include testing more accurate models of infection for this novel activity and identifying new compounds that can be used alongside bicyclomycin to stop resistance developing. Bicyclomycin is a molecule that is made naturally by non-pathogenic soil bacteria. Natural products such as this are produced by the action of a series of enzymes (proteins), which are encoded by genes (DNA) in the bacterial genome. Thus, we aim to discover the genes that are responsible for bicyclomycin production. This discovery will allow us to make modifications to the pathway to make more of the compound, which will enable its study in infection models. We can also modify the pathway to produce new versions of bicyclomycin, which might have better activity than the original compound or overcome resistance mechanisms.

抗生素已经从传染病中拯救了数百万人的生命，可以说是20世纪世纪最伟大的医学发现。不幸的是，21世纪世纪对公共卫生的最大威胁之一是多重耐药细菌感染的兴起。这一增长是由于抗生素在医学和农业中的不当使用以及新型抗生素的发现不足造成的。这促使世界卫生组织警告说，“由于缺乏新的抗生素进入市场，采取行动避免全球医疗危机的必要性越来越紧迫”，英国首席医疗官Dame Sally Davies教授宣布，“我们也没有足够快地开发新药”。这是一个全球性问题，需要采取全球行动，特别是在治疗多重耐药革兰氏阴性细菌感染方面。革兰氏阴性菌对临床上使用的许多抗生素具有天然耐药性，并且在使用这些药物治疗多年后已经进化为对大多数其他抗生素具有耐药性。有各种方法来解决这个日益严重的问题，包括重新利用“旧”抗生素。这些药物在人体临床试验中进行了彻底的疗效和安全性测试，但由于各种原因没有广泛使用。例如，当时可能已有更好的广谱替代品。多药耐药性的出现意味着这些分子现在可能非常有用，特别是因为它们缺乏临床应用意味着致病细菌没有机会产生耐药性。此外，新的实验有时可以揭示早期研究中未发现的抗菌活性。双环霉素就是这种情况，双环霉素是一种古老的抗生素，以前曾被证明对革兰氏阴性菌具有中等的抑菌活性。“抑菌”意味着抗生素阻止细菌生长，但不会主动杀死细菌，这可能导致感染的持续。令人兴奋的是，最近的研究表明，双环霉素实际上可以杀死细菌（“杀菌”），当它与另一种抑菌抗生素一起使用时。当与另一种药物联合使用时，这种意想不到的活性使双环霉素成为治疗革兰氏阴性细菌感染的非常有前途的抗生素。因此，我们建议开展进一步的工作，以确定双环霉素是否可以在临床上广泛使用。这将包括测试这种新活性的更准确的感染模型，并确定可与双环霉素一起使用以阻止耐药性发展的新化合物。双环霉素是一种由非病原性土壤细菌天然产生的分子。像这样的天然产物是由一系列酶（蛋白质）的作用产生的，这些酶由细菌基因组中的基因（DNA）编码。因此，我们的目标是发现负责双环霉素生产的基因。这一发现将使我们能够修改该途径以产生更多的化合物，这将使其能够在感染模型中进行研究。我们还可以修改该途径以产生新版本的双环霉素，其可能具有比原始化合物更好的活性或克服抗性机制。

项目成果

Bicyclomycin Activity against Multidrug-Resistant Gram-Negative Pathogens.

• DOI: 10.1128/spectrum.03790-22
• 发表时间: 2023-02-14
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Towards the sustainable discovery and development of new antibiotics.

• DOI: 10.1038/s41570-021-00313-1
• 发表时间: 2021
• 期刊: Nature reviews. Chemistry
• 作者: Miethke M;Pieroni M;Weber T;Brönstrup M;Hammann P;Halby L;Arimondo PB;Glaser P;Aigle B;Bode HB;Moreira R;Li Y;Luzhetskyy A;Medema MH;Pernodet JL;Stadler M;Tormo JR;Genilloud O;Truman AW;Weissman KJ;Takano E;Sabatini S;Stegmann E;Brötz-Oesterhelt H;Wohlleben W;Seemann M;Empting M;Hirsch AKH;Loretz B;Lehr CM;Titz A;Herrmann J;Jaeger T;Alt S;Hesterkamp T;Winterhalter M;Schiefer A;Pfarr K;Hoerauf A;Graz H;Graz M;Lindvall M;Ramurthy S;Karlén A;van Dongen M;Petkovic H;Keller A;Peyrane F;Donadio S;Fraisse L;Piddock LJV;Gilbert IH;Moser HE;Müller R
• 通讯作者: Müller R

Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes.

• DOI: 10.1128/aem.02828-17
• 发表时间: 2018-05-01
• 期刊: Applied and environmental microbiology
• 影响因子: 4.4
• 作者: Vior NM;Lacret R;Chandra G;Dorai-Raj S;Trick M;Truman AW
• 通讯作者: Truman AW