understand how the lung environment affects colistin treatment efficacy and to develop new therapeutic strategies to improve patient outcomes

了解肺部环境如何影响粘菌素治疗效果并开发新的治疗策略以改善患者的治疗效果

• 批准号: 2767794
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2767794
• 关键词: understand; how; lung; environment; affects

Cystic fibrosis (CF) affects >10,000 people in the UK. Early mortality characterises the disease, largelydriven by chronic lung infection and inflammatory airway wall damage. By adulthood >60% patientsare chronically infected with the Gram-negative organism, Pseudomonas aeruginosa (Pa). Currenttherapy is limited, and once infection is chronic, the best that can be achieved is 'suppression' ofbacterial load, usually with inhaled antimicrobials. The Strategic Research Centre for Pa infectionwas established by Prof Jane C Davies, with a focus on improving understanding of pathogenicmechanisms and therapies. Its partnership with the Royal Brompton Hospital's CF clinic, one of thelargest in Europe, through senior clinical academics, underpins the strong translational focus of theprogramme. The narrow pipeline of new antibiotics under development means that work to improveefficacy of existing agents is urgently needed.Colistin is the polymyxin antibiotic used most commonly to control chronic P. aeruginosa infection inCF. Unfortunately, whilst colistin is usually effective in suppressing infection, it is almost never ableto clear P. aeruginosa from the lungs once chronic infection is established. Intravenous colistin isalso used as a 'last-resort' agent in severe disease, and thus, the emergence of resistance topolymyxin antibiotics is a growing concern. Efforts to improve colistin efficacy have been hamperedby a poor understanding of the antibiotic's mode of action and the lack of knowledge around theimpact that the host environment has on bacterial susceptibility. Recent work from the Edwards lab,based in the MRC Centre for Molecular Bacteriology and Infection, has revealed that colistin targetsLPS in both the outer and cytoplasmic membranes, leading to bacterial lysis and killing (Sabnis et al.,2019). We have also shown that colistin resistance due to the mobile colistin resistance (MCR) familyof LPS modifying enzymes (Liu et al., 2016) is due to modification of LPS at the cytoplasmicmembrane (Sabnis et al., 2019).We exploited this information to develop a combination therapeutic approach to enhance colistinactivity. We found that the experimental antibiotic murepavadin caused the accumulation of LPS inthe cytoplasmic membrane of P. aeruginosa, which sensitised the bacterium >1000-fold to colistin mediated killing. Given the geographical heterogeneity in airway deposition of inhaled agentsrelated to airway narrowing and mucus plugging, and the resulting variability in drug concentrations,successful approaches to enhance efficacy of lower drug concentrations could have direct clinicalimpact.The crucial next step in this work is to determine how the host environment influences LPSprocessing and transport, which we hypothesise will have significant effects on colistin susceptibilityand therefore treatment outcomes. For example, during this work, we found that LPS released bybacteria exposed to colistin can sequester the antibiotic, rendering it ineffective. We also found thatthe presence of human serum renders P. aeruginosa tolerant of colistin. These findings indicate thatcolistin efficacy is affected by the in vivo environment, but this requires further investigation.

囊性纤维化（CF）影响英国超过10，000人。早期死亡率是该病的特征，主要由慢性肺部感染和气道壁炎症损伤引起。到成年时，>60%的患者慢性感染革兰氏阴性菌铜绿假单胞菌（Pa）。目前的治疗是有限的，一旦感染是慢性的，最好的方法是“抑制”细菌负荷，通常是吸入抗菌剂。Pa感染战略研究中心由Jane C Davies教授成立，重点是提高对致病机制和治疗方法的理解。它与皇家布朗普顿医院的CF诊所，在欧洲最大的之一，通过高级临床学者的合作伙伴关系，巩固了该计划的强大的翻译重点。开发中的新抗生素的管道狭窄意味着迫切需要提高现有药物的疗效。多粘菌素是最常用于控制CF中慢性铜绿假单胞菌感染的多粘菌素抗生素。不幸的是，虽然粘菌素通常能有效抑制感染，但一旦慢性感染建立，它几乎无法从肺部清除铜绿假单胞菌。静脉注射粘菌素也被用作重症患者的最后手段，因此，多粘菌素抗生素耐药性的出现越来越受到关注。由于对抗生素的作用方式了解不多，以及缺乏对宿主环境对细菌敏感性影响的了解，提高粘菌素疗效的努力受到了阻碍。来自MRC分子细菌学和感染中心的Edwards实验室的最近工作揭示了粘菌素靶向外膜和细胞质膜中的LPS，导致细菌裂解和杀死（Sabnis等人，2019年）。我们还表明，由于LPS修饰酶的移动的粘菌素抗性（MCR）家族，2016）是由于LPS在细胞质膜上的修饰（Sabnis等人，我们利用这些信息开发了一种联合治疗方法，以增强colistinactivity。我们发现，实验性抗生素murepavadin导致LPS在铜绿假单胞菌的细胞质膜上积累，这使细菌对粘菌素介导的杀伤作用敏感1000倍以上。考虑到与气道狭窄和粘液堵塞相关的吸入剂气道沉积的地理异质性，以及由此导致的药物浓度的可变性，提高较低药物浓度疗效的成功方法可能具有直接的临床影响。这项工作的关键下一步是确定宿主环境如何影响LPS的加工和运输，我们假设这将对粘菌素的耐受性和治疗结果产生显著影响。例如，在这项工作中，我们发现细菌暴露于粘菌素后释放的LPS可以隔离抗生素，使其无效。我们还发现人血清的存在使铜绿假单胞菌对粘菌素耐受。这些发现表明粘菌素的疗效受体内环境的影响，但这需要进一步研究。