Targets for Design of Drug Combinations that Select against Antibiotic Resistance

选择对抗抗生素耐药性的药物组合的设计目标

• 批准号: 8825739
• 负责人: Adilson E Motter
• 金额: $ 30万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825739
• 关键词: Address; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Biological Models; Cause of Death; Clinic; Combination Drug Therapy; Combined Antibiotics; Development; Disease; Drug Combinations; Drug Targeting; Drug resistance; Escherichia coli; Escherichia coli K12; Explosion; Future Generations; Gene Combinations; Gene Deletion; Gene Targeting; Genes; Genetic; Goals; Infection; Methodology; Microbe; Microbiology; Pharmaceutical Preparations; Research; Resistance; System; Validation; cancer cell; chemotherapy; combinatorial; design; innovation; mathematical model; microbial; novel; pathogen; predictive modeling; public health relevance

DESCRIPTION (provided by applicant): This collaborative project will develop and integrate complementary mathematical and experimental microbiology approaches to identify gene targets for the design of antibiotic drug combinations that can select against resistance. Diseases caused by microbial infection are the second leading cause of death worldwide. A major challenge in the treatment of such infections is the development of new classes of antibiotics. Inevitably, the introduction of a new antibiotic into the clinic is accompanied by the emergence of resistant microbes. There are, therefore, two major issues to consider in the development of new antibiotic drugs: 1) the identification of novel targets and 2) the discovery of approaches that will limit the emergence of resistance. The major goal of this project is to develop and apply an innovative methodology that can address these two problems simultaneously. The proposed research builds on the recent discovery that the combination of two antagonistically interacting antibiotics (where one drug suppresses the effect of the other) can select against antibiotic resistance. The applicability of this concept has been limited by the fact that most existing antibiotics do not have a known antagonistic partner. The specific aims are thus to develop approaches that will allow us a) to identify gene targets for the design of antagonistic drugs for existing antibiotics and b) to identify paired gene targets that would permi the development of novel antagonistically-interacting drug pairs. This will be achieved by systematically identifying synthetic rescues, which are genetic interactions whereby the negative phenotypic effect of a gene deletion can be partially compensated by the targeted inactivation of other genes. Such rescues are the genetic counterpart of antagonistically interacting drugs and, as such, present potential targets for the development of novel, antagonistic drug combination therapies that can select against drug resistance. To overcome the combinatorial explosion in the number of possible gene-gene combinations in a bacterium, the discovery of such desired drug targets will be guided by new predictive modeling integrated with directed experimental validation. The project will be focused on Escherichia coli K12, which is a robust experimental system that is amenable to mathematical modeling.

描述（由申请人提供）：该合作项目将开发和整合互补的数学和实验微生物学方法，以确定基因靶标，用于设计可以选择对抗耐药性的抗生素药物组合。由微生物感染引起的疾病是全世界第二大死亡原因。治疗此类感染的一个主要挑战是开发新型抗生素。不可避免地，新抗生素引入临床的同时， 耐药微生物的出现。因此，在开发新的抗生素药物时需要考虑两个主要问题：1）新靶点的识别；2）新靶点的发现。 限制阻力出现的方法。该项目的主要目标是开发和应用一种可以同时解决这两个问题的创新方法。这项拟议的研究建立在最近发现的基础上，即两种拮抗相互作用的抗生素（一种药物抑制另一种药物的作用）的组合可以选择对抗抗生素耐药性。这一概念的适用性受到以下因素的限制： 事实上，大多数现有抗生素没有已知的拮抗伙伴。因此，具体目标是开发方法，使我们能够a）识别现有抗生素拮抗药物设计的基因靶标，b）识别允许开发新型拮抗相互作用药物对的成对基因靶标。这将通过系统地识别合成拯救来实现，合成拯救是遗传相互作用，基因删除的负面表型效应可以通过其他基因的有针对性的失活来部分补偿。这种拯救是拮抗相互作用药物的基因对应物，因此，为开发能够选择对抗耐药性的新型拮抗药物组合疗法提供了潜在的目标。为了克服细菌中可能的基因-基因组合数量的组合爆炸，此类所需药物靶标的发现将通过与定向实验验证相结合的新预测模型来指导。该项目将重点关注大肠杆菌 K12，这是一个强大的实验系统，适合数学建模。