Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii

项目摘要 鲍曼不动杆菌已经成为一个主要的医疗保健问题，部分原因是这种生物的倾向 对一线抗生素产生抗药性。鲍曼不动杆菌耐药谱包括氨基糖苷类和β-内酰胺类 修饰因子，但主要由6个不同泵的至少40个药物外排系统组成 家人。固有的多药耐药是通过突变导致一个或多个外排的过度表达而发生的 系统，从而允许有机体从细胞中排出抗生素。最近我们发现了外流 系统还调节适应性鲍曼不动杆菌的抗生素耐药性。意思是，转移敏感的抗生素 菌株对生理相关的生长条件，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 是可以在病人体内实现的。这种现象被称为适应性外排介导的抵抗。 Handcock和他的同事们提出的(AEMR)，已经被假设为一种否则会产生抗生素的方法 在诊所内，敏感菌株对抗生素治疗没有反应。我们假设这种过度外流 AEMR疾病的表型将提供一个独特和创新的筛选平台，以确定广泛的 能抑制多个鲍曼不动杆菌外排泵的光谱外排泵抑制剂。事实上，一个高吞吐量的试点 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中的抗生素耐药性，这些外排泵是臭名昭著的多药病因 临床分离株的耐药性。我们在这里的目标是1。扩大我们的筛查方法，以包括更大的、 化学多样化的化合物文库将获得鲍曼不动杆菌外排泵抑制剂的额外化学系列 (Epis)，2.用药物化学优化苯磺酰胺和多达两种附加化学品 系列EPIS，3.定义苯磺酰胺类的细胞靶标和EPIS的新化学类别，以及 4.检测先导化合物对外排介导的鲍曼不动杆菌的体内药效 多药耐药。

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.