Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii

鲍曼不动杆菌适应性外排介导的耐药性抑制剂

基本信息

批准号：
10625029
负责人：
Paul Dunman
金额：
$ 71.54万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-07 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625029
关键词：
Acinetobacter baumannii Address Adjuvant Aminoglycosides Antibiotic Resistance Antibiotic Therapy Antibiotic susceptibility Antibiotics Biological Biological Assay Carbapenems Cells Chemicals Chemosensitization Clinic Clinical Communicable Diseases Compensation Disease Outbreaks Drug Efflux Drug Kinetics ESKAPE pathogens Exhibits Failure Family Fluoroquinolones Frequencies Genetic Goals Growth Healthcare Human Incidence Infection Laboratories Libraries Mediating Molecular Multi-Drug Resistance Mutation Organism Patients Pharmaceutical Chemistry Phenotype Physiological Property Pump Reducing Agents Reporting Resistance Resistance development Septicemia Series Serum Severities Societies Structure System Systemic infection Tetracyclines Therapeutic Agents Toxic effect Translations Up-Regulation World Health Organization analog antibiotic efflux benzenesulfonamide beta-Lactams cellular targeting design efflux pump extensive drug resistance glycylcycline high throughput screening improved in vivo in vivo Model in vivo evaluation inhibitor innovation interest lead optimization member mortality mouse model overexpression pathogen pathogenic bacteria patient population resistant strain response scaffold screening small molecule tigecycline ventilator-associated pneumonia

项目摘要

PROJECT ABSTRACT Acinetobacter baumannii has emerged as a major healthcare concern due, in part, to the organism’s propensity to develop resistance to front-line antibiotics. The A. baumannii resistome includes aminoglycoside and β-lactam modifying factors, but is primarily comprised of at least 40 drug efflux systems belonging to 6 distinct pump families. Intrinsic multidrug resistance occurs via mutations that lead to overexpression of one or more efflux systems, thereby allowing the organism to extrude antibiotics from the cell. Recently we discovered efflux systems also modulate adaptive A. baumannii antibiotic resistance. Meaning, transfer of antibiotic susceptible strains to physiologically relevant growth conditions, such as human serum, leads to the upregulation of at least 18 annotated efflux pump components, which in turn allows for efflux mediated resistance to antibiotic levels that are achievable within a patient. This phenomenon, which has been termed adaptive efflux mediated resistance (AEMR) by Handcock and colleagues, has been hypothesized to be one means by which otherwise antibiotic susceptible strains fail to respond to antibiotic treatment within the clinic. We hypothesized that the hyper-efflux phenotype of AEMR conditions would provide a unique and innovative screening platform to identify broad- spectrum efflux pump inhibitors that inhibit multiple A. baumannii efflux pumps. Indeed, a pilot high throughput screen led to the identification of the benzenesulfonamide class of efflux pump inhibitors that eliminate AEMR and antibiotic resistance within strains that overexpress efflux pumps that are notorious causes of multidrug resistance among clinical isolates. Our goals herein are to 1. Expand our screening approach to include a larger, chemically diverse compound library to arrive at additional chemical series of A. baumannii efflux pump inhibitors (EPIs), 2. Use medicinal chemistry to optimize the benzenesulfonamide and as many as two additional chemical series of EPIs, 3. Define the cellular target of the benzenesulfonamides and new chemical classes of EPIs, and 4. Test the in vivo efficacy of front runner compounds against A. baumannii strains that exhibit efflux mediated multidrug resistance.

项目摘要鲍曼不动杆菌已成为一个主要的医疗保健问题，部分原因是该生物体的倾向产生对一线抗生素的耐药性。鲍曼不动杆菌耐药组包括氨基糖苷和β-内酰胺。修改因素，但主要由属于 6 个不同泵的至少 40 个药物流出系统组成内在的多药耐药性是通过导致一种或多种外排过度表达的突变而发生的。最近我们发现了外流。系统还调节适应性鲍曼不动杆菌抗生素耐药性，即抗生素敏感性的转移。菌株适应生理相关的生长条件，例如人血清，导致至少上调 18 个带注释的外排泵组件，这反过来又允许外排介导的对抗生素水平的耐药性这种现象在患者体内是可以实现的，被称为适应性外流介导的抵抗。 Handcock 及其同事提出的（AEMR）已被削弱为抗生素的一种手段我们利用了过度外流的特点，发现敏感菌株对诊所内的抗生素治疗没有反应。 AEMR 条件的表型将提供一个独特且创新的筛选平台来识别广泛的抑制多个鲍曼不动杆菌外排泵的光谱外排泵抑制剂确实是一个试点高通量。筛选导致鉴定出消除 AEMR 的苯磺酰胺类外排泵抑制剂以及过度表达外排泵的菌株内的抗生素耐药性，这是多种药物的臭名昭著的原因我们的目标是 1. 扩大我们的筛选方法，以包括更大范围的、化学多样化的化合物库，以获得鲍曼不动杆菌外排泵抑制剂的其他化学系列 (EPI)，2. 使用药物化学来优化苯磺酰胺和多达两种其他化学品系列 EPI，3. 定义苯磺酰胺类药物的细胞靶点和 EPI 的新化学类别，以及 4. 测试领跑者化合物对表现出外排介导的鲍曼不动杆菌菌株的体内功效多重耐药性。