Safer aminoglycoside therapeutics by biosynthetic engineering

通过生物合成工程开发更安全的氨基糖苷类疗法

• 批准号: G1001687/1
• 负责人: Peter Leadlay
• 金额: $ 50.49万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1001687%2F1
• 关键词: Safer; aminoglycoside; therapeutics; biosynthetic; engineering

Bacterial infections in hospital patients can lead to sepsis, in which an overwhelming infection of the bloodstream by toxin-producing bacteria becomes life-threatening. Very few new antibiotics are being developed, and so the established antibiotic gentamicin, discovered over 40 years ago, is likely to remain a vital mainstay in efforts to combat sepsis. Unfortunately there are real dangers associated with its use: a large percentage of patients treated with gentamicin, or related antibiotics, develop acute kidney failure (nephrotoxicity). The drug may also cause irreversible hearing loss (ototoxicity). Treatment is very costly because patients have to be closely monitored to minimise these severe side-effects. Sustained efforts are being made to research ways of minimising the side-effects of gentamicin, by altering the dosing strategy for example; and to understand the biochemical mechanisms by which the kidney and the inner ear are damaged. Unfortunately the gentamicin used clinically is a mixture of compounds and different batches of commercial gentamicin have different amounts of each component. The individual components can be separated on a small scale but it has not been economically viable to do this commercially. It was believed that they were equally effective and equally toxic, but in 2006, researchers in the USA re-tested each of the main components of gentamicin (known as C1, C1a, C2 and C2a) and showed that, surprisingly, purified component C2 is fully effective as an antibiotic - but is apparently not nephrotoxic at all (at least in rats). The aim of this project is to decipher all of the individual steps of the late stages of gentamicin biosynthesis, to identify which enzymes are involved, and to devise strategies for engineering specific genes in the pathway in order to divert production towards a single component (such as C2). The ready availability of single components of the gentamicin complex by fermentation would encourage potentially safer formulations of the antibiotic to be tested. Since gentamicins and related aminoglycosides are also promising agents for the correction of certain human genetic diseases, such as cystic fibrosis and the muscle-wasting disease Duchenne muscular dystrophy, there could be wider medical benefits too.

医院患者的细菌感染可导致败血症，其中产生毒素的细菌对血流的压倒性感染变得危及生命。很少有新的抗生素被开发出来，因此40多年前发现的抗生素庆大霉素可能仍然是对抗败血症的重要支柱。不幸的是，它的用途：有真实的危险：大部分用庆大霉素或相关抗生素治疗的患者发生急性肾衰竭（肾毒性）。该药物也可能导致不可逆的听力损失（耳毒性）。治疗费用非常昂贵，因为必须密切监测患者，以尽量减少这些严重的副作用。人们正在不断努力研究如何通过改变给药策略等方式最大限度地减少庆大霉素的副作用;并了解肾脏和内耳受损的生化机制。不幸的是，临床上使用的庆大霉素是化合物的混合物，并且不同批次的商业庆大霉素具有不同量的每种组分。单个组分可以小规模分离，但在商业上这样做在经济上不可行。人们认为它们同样有效，同样有毒，但在2006年，美国的研究人员重新测试了庆大霉素的每种主要成分（称为C1，C1 a，C2和C2 a），并显示，令人惊讶的是，纯化的成分C2作为抗生素是完全有效的-但显然根本没有肾毒性（至少在大鼠中）。该项目的目的是破译庆大霉素生物合成后期阶段的所有单个步骤，以确定涉及哪些酶，并设计用于工程化途径中特定基因的策略，以便将生产转向单一组分（如C2）。庆大霉素复合物的单一组分通过发酵容易获得，这将鼓励潜在的更安全的抗生素制剂进行测试。由于庆大霉素和相关的氨基糖苷类药物也是矫正某些人类遗传疾病的有前途的药物，如囊性纤维化和肌肉萎缩性疾病杜氏肌营养不良症，因此也可能有更广泛的医疗益处。