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Development of a complete pathway model for the synthesis of the gram negative cell

开发革兰氏阴性细胞合成的完整途径模型

基本信息

批准号：
133117
负责人：
金额：
$ 8.92万
依托单位：
OPPILOTECH LTD
依托单位国家：
英国
项目类别：
Feasibility Studies
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=133117
关键词：
Development complete pathway model synthesis

项目摘要

It is predicted that within the next 33 years, deaths attributable to antibiotic resistant bacteria will outnumber those caused by cancer. This problem is compounded by the lack of both the discovery and development of novel antimicrobial molecules. Of particular concern are the resistance levels exhibited by the Gram -ve bacterial species such as E.coli, Kelbsiella and pseudomonas. Oppilotech are developing a computational platform in order to facilitate the detection of novel antimicrobial targets against Gram-ve bacteria. We have used this method successfully to identify new targets which weaken the cell wall structures making them more permeable to existing drugs. This potentiating approach has the capacity to reactivate drugs which are no longer used because of high resistance levels. It can also reduce the doses at which antimicrobials are given, particularly important for drugs with know toxicity issues (such as colistin). Finally, this approach may facilitate the use of Gram +ve drugs for Gram -ve infections. If funded Oppilotech will use the award to employ a computational biologist to expand the existing model in order to incorporate peptidoglycan synthesis. This will effectively complete all of the main cytoplasmic steps involved in the synthesis of the bacterial cell envelope. Once complete this deterministic model will be linked with a spatial model with the aim of determining the most optimal drug target in terms of potentiating activity.

据预测，在未来33年内，由抗生素耐药性细菌造成的死亡人数将超过癌症造成的死亡人数。由于缺乏新的抗微生物分子的发现和开发，这个问题变得更加复杂。特别关注的是革兰氏细菌物种如大肠杆菌、克雷伯氏菌和假单胞菌表现出的抗性水平。Oppilotech正在开发一个计算平台，以促进针对革兰氏菌的新型抗菌靶标的检测。我们已经成功地使用这种方法来识别新的靶点，这些靶点削弱了细胞壁结构，使它们对现有药物更具渗透性。这种增强方法有能力重新激活由于高耐药性而不再使用的药物。它还可以减少抗生素的剂量，特别是对于已知毒性问题的药物（如粘菌素）。最后，这种方法可能有助于使用革兰氏+ve药物治疗革兰氏-ve感染。如果获得资助，Oppilotech将利用该奖项聘请计算生物学家扩展现有模型，以纳入肽聚糖合成。这将有效地完成细菌细胞包膜合成中涉及的所有主要细胞质步骤。一旦完成，该确定性模型将与空间模型相关联，目的是确定增强活性方面的最佳药物靶标。