2023 Multi-Drug Efflux Systems: Targeting the Mechanisms and Regulation of Multi-Drug Transporters for Advancing Health during a Pandemic GRC/GRS

项目摘要 活性药物从细胞外排导致的多药耐药是临床上主要的抗肿瘤药物耐药障碍之一。 癌症化疗和传染病的治疗。世界卫生组织最新监测数据 该组织发现，在世界上一些最常见的，可能是 最危险的病原体，包括引起腹泻和呼吸道疾病的病原体、疟疾和 肺结核。抗药性病原体的日益增长的威胁增加了一个没有有效药物的世界的前景 抗菌药，使患者容易感染以前可以治疗的传染病。多药外排 系统已经进化，以保护微生物和人类免受有害的异生物质和有毒代谢物的伤害。 它们调节外来物质的吸收、分布和排泄，并在人体内保护避难所组织。 通过调节药物对血脑、血胎盘和血睾丸屏障的通透性。此外, 转运蛋白也是决定药物反应的主要因素，从药理疗效到毒性， 并参与宿主与病原体的相互作用。从而对多药外排有了更全面的认识 系统对于设计更有效的治疗并改善患者结果至关重要。 该提案要求部分支持戈登研究会议(GRC)和戈登 多药物外流系统研究研讨会(GRS)将于3月25日至3月在德克萨斯州加尔维斯顿举行 2023年3月31日。这次会议的主要目标是将来自传统上两个国家的研究人员聚集在一起 孤立的领域，原核生物和真核生物的转运体领域，跨越各种学科 (微生物学、化学、药理学、医学和临床研究)，相互学习。九 口头陈述的会议和四个海报会议将促进新的 研究人员、该领域的领导者以及在学术界、制药和生物技术领域工作的同事 工业。第二个目标是传播技术进步和变革性方法。 会议将重点介绍最近在理解结构-功能关系、确定 药物结合部位、药物外排机制和转运体的药理学靶向 包括新的药物输送策略。长期目标是开发更具体、更有效的药物。 抑制、调节或逃避多方面的外排系统。进一步的重点将放在监管 局部和全局调节因子介导的外排系统与基因表达的多层次调控 对特定环境线索的反应。第三个目标是指导早期职业科学家，整合 来自少数族裔背景的妇女和科学家，并提供学习环境和支持系统 对该领域未来领导者的发展至关重要。总体而言，这次会议将促进在 多药外排系统在逆转多药耐药性和促进全球健康方面的科学前沿。

Project Summary Multidrug resistance caused by active drug efflux from cells is one of the major clinical impediments in anti- cancer chemotherapy and treatment of infectious diseases. New surveillance data by the World Health Organization reveals widespread antibiotic resistance in some of the world's most common, and potentially most dangerous, pathogens including those causing diarrheal and respiratory diseases, malaria and tuberculosis. The growing threat of drug-resistant pathogens raises the prospect of a world without effective antimicrobials, where patients are left vulnerable to previously treatable infectious diseases. Multidrug efflux systems have evolved to protect microorganisms and humans from harmful xenobiotics and toxic metabolites. They regulate absorption, distribution, and excretion of xenobiotics, and in humans, protect sanctuary tissues by regulating the drug permeability of the blood-brain, blood-placenta and blood–testis barriers. In addition, transporters are also major players in dictating responses to drugs, from pharmacological efficacy to toxicity, and are involved in host-pathogen interactions. Thus, a more complete understanding of multidrug efflux systems is of paramount important for the design of more effective treatments with improved patient outcomes. This proposal requests partial support for the Gordon Research Conference (GRC) and Gordon Research Seminar (GRS) on Multi-Drug Efflux Systems to be held in Galveston, Texas, March 25 – March 31, 2023. The primary goal of this conferences is to bring together researchers from two traditionally isolated fields, the prokaryotic and eukaryotic transporter fields, working across a variety of disciplines (microbiology, chemistry, pharmacology, medicine, and clinical research), to learn from each other. Nine sessions of oral presentations, and four poster sessions will foster scientific interactions between new investigators, leaders in the field, and colleagues working in academia, the pharmaceutical and biotechnology industries. The second goal is to disseminate technological advances and transformative approaches. Sessions will highlight recent innovations in the understanding of structure-function relations, the identification of the drug binding sites, and drug-efflux mechanics, and the pharmacological targeting of transporters including novel drug delivery strategies. The long-term goal is to develop more specific and more potent drugs that inhibit, modulate or evade the multifaceted efflux systems. Further emphasis will be on the regulation of efflux systems mediated by local and global regulators and the multilayered control of gene expression in response to specific environmental cues. The third goal is to mentor early career scientists, integrate women and scientists from minority backgrounds, and provide a learning environment and support system critical for development of future leaders of the field. Overall, this conference will foster discussions at the frontiers of science in multidrug efflux systems for reversing multidrug resistance and advancing global health.