Targeting Exotoxin U with repurposed drugs to improve the clinical outcomes of Pseudomonas aeruginosa infections.
利用重新利用的药物靶向外毒素 U,以改善铜绿假单胞菌感染的临床结果。
基本信息
- 批准号:MR/W024624/1
- 负责人:
- 金额:$ 33.76万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 财政年份:2022
- 资助国家:英国
- 起止时间:2022 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Pseudomonas aeruginosa (Pseudomonas) is a bacteria which causes a wide variety of infections, including corneal (eye), lung and blood, resulting in significant disability and death worldwide. A recent surge in antibiotic-resistant Pseudomonas has prompted the World Health Organisation to advise new treatments must be developed as a 'high priority'. Recovery for many patients remains very poor even if their condition is treatable with antibiotics. For those with corneal (transparent window at the front the eye) infections, significant damage and scarring can lead to blindness. In Pseudomonas infections with poor outcomes it has been established that the bacteria inject a toxin, called Exotoxin U (ExoU), into human cells. ExoU rapidly kills the cells including immune cells sent to fight the infection. The bacteria evade the immune system to continue multiplying and causing damage. Inhibiting ExoU could provide a new treatment to reduce the severity, disability and death caused by this bacteria.We have identified 25 promising drugs which specifically inhibit ExoU. In test-tube models of corneal infections, the drugs reduce damage and show protective effects which help the cells heal. This occurs even at very low concentrations. Our data suggests they can be combined with antibiotics to improve these results. Significant research is required prior to human trials. This includes testing different concentrations, combinations, assessing how well they get to the site of infection, and testing them in clinically-relevant animal models. Protocols for administration are also required, including strength, frequency and length of the course. Demonstrating they work for infections in other organs, such as the lung, would prove they could be developed to treat and benefit more patients. My fellowship project will build on our initial work, with the following aims and objectives:1) I will evaluate the ExoU inhibiting drugs in scratch and infection cell models, primarily in eye cells, but also lung cells to see if they will work in these too. Different concentrations and combinations will be tested, with and without antibiotics. Results will demonstrate their potential and help develop the treatment protocols. 2) I will measure the concentration of the ExoU inhibiting drugs that get to the site of infection. I will utilise a model which uses a donor human cornea attached to a glass artificial model of the anterior chamber of the eye (the front part which contains fluid). The drug, as an eye-drop, will be applied to the surface, and samples of the fluid within will be taken at different time-points. The concentration of drug in these samples will be measured. This is important information which will aid the development of the treatment protocols and advance the drugs towards human trials.3) I will evaluate the ExoU inhibiting drugs in a more advanced infection model. Pig corneas (by-products of the food industry) will be infected with Pseudomonas and treated with the ExoU inhibitors using the protocols developed in objectives 1 and 2. This will help identify the most promising drugs and refine the treatment protocol which will be used in further experiments. Conducting this experiment will significantly reduce the number of animals required in subsequent experiments. 4) When I have identified the two best drugs and protocols, I will evaluate these further in a mouse model of corneal infection. This work will be conducted with my collaborators in the United States who have an ethically approved model and the expertise. These experiments will provide the necessary data, including the safety data, which we will require to proceed to human clinical trials. My project will significantly develop the knowledge required to progress these ExoU inhibiting drugs towards human trials. The ultimate aim is that the drugs will be used to treat patients with Pseudomonas infections to improve their recovery and overall outcome.
铜绿假单胞菌是一种引起多种感染的细菌,包括角膜(眼)、肺和血液,在世界范围内导致严重的残疾和死亡。最近耐药假单胞菌的激增促使世界卫生组织建议必须将开发新的治疗方法作为“高度优先”。许多患者的恢复情况仍然非常差,即使他们的病情可以用抗生素治疗。对于那些有角膜(眼睛前面的透明窗口)感染的人来说,严重的损伤和疤痕可能会导致失明。在预后较差的假单胞菌感染中,已证实这种细菌向人类细胞注入一种名为外毒素U(Exooxin U,ExoU)的毒素。ExoU迅速杀死包括被送去对抗感染的免疫细胞在内的细胞。这种细菌逃避免疫系统,继续繁殖并造成损害。抑制ExoU可以提供一种新的治疗方法来降低这种细菌造成的严重程度、残疾和死亡。我们已经确定了25种有希望的药物来专门抑制ExoU。在角膜感染的试管模型中,这些药物减少了损害,并显示出帮助细胞愈合的保护作用。即使在非常低的浓度下也会发生这种情况。我们的数据表明,它们可以与抗生素联合使用来改善这些结果。在进行人体试验之前,需要进行重要的研究。这包括测试不同的浓度、组合,评估它们到达感染部位的情况,并在临床相关的动物模型中测试它们。还需要制定管理方案,包括强度、频率和疗程长度。证明它们对其他器官的感染有效,如肺部,将证明它们可以被开发出来治疗更多的患者并使其受益。我的奖学金项目将建立在我们最初工作的基础上,目标如下:1)我将评估ExoU抑制药物在划痕和感染细胞模型中的作用,主要是在眼细胞,但也包括肺细胞,看看它们是否也适用于这些细胞。将测试不同的浓度和组合,包括使用和不使用抗生素。结果将展示它们的潜力,并有助于制定治疗方案。2)测量到达感染部位的ExoU抑制药物的浓度。我将使用一个模型,该模型将捐赠者的角膜连接到一个玻璃人工眼前房模型(前房含有液体)。这种药物将作为眼药水涂在皮肤表面,并在不同的时间点采集体内液体的样本。这些样本中的药物浓度将被测量。这是有助于开发治疗方案并将药物推向人体试验的重要信息。3)我将在更高级的感染模型中评估ExoU抑制药物。猪角膜(食品工业的副产品)将感染假单胞菌,并使用目标1和2中制定的方案使用ExoU抑制剂进行治疗。这将有助于确定最有希望的药物,并改进将在进一步实验中使用的治疗方案。进行这项实验将大大减少后续实验所需的动物数量。4)当我确定了两种最好的药物和方案后,我将在小鼠角膜感染模型中进一步评估这些药物和方案。这项工作将与我在美国的合作者一起进行,他们拥有道德认可的模式和专业知识。这些实验将提供必要的数据,包括我们进行人体临床试验所需的安全性数据。我的项目将极大地发展使这些ExoU抑制药物进入人体试验所需的知识。最终目的是将这些药物用于治疗假单胞菌感染患者,以改善他们的康复和总体结果。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Keri McLean其他文献
Evaluation of ExoU inhibitors in a Pseudomonas aeruginosa scratch infection assay
ExoU 抑制剂在铜绿假单胞菌划痕感染测定中的评价
- DOI:
10.1101/2020.06.24.170373 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
D. Foulkes;Keri McLean;Joscelyn Harris;A. Haneef;D. Fernig;C. Winstanley;N. Berry;S. Kaye - 通讯作者:
S. Kaye
A phospholipase assay screen identifies synergistic inhibitors of the P. aeruginosa toxin ExoU
磷脂酶测定筛选鉴定铜绿假单胞菌毒素 ExoU 的协同抑制剂
- DOI:
10.1101/2022.02.21.481271 - 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
D. Foulkes;Keri McLean;A. Hermann;James Johnson;C. Winstanley;N. Berry;D. Fernig;S. Kaye - 通讯作者:
S. Kaye
Hepatitis B in a vaccinated soldier: a case report
一名接种疫苗的士兵感染乙型肝炎:病例报告
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Keri McLean;T. Elmer;D. Freshwater;L. Lamb;S. D Woolley - 通讯作者:
S. D Woolley
Keri McLean的其他文献
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