UPTAKE OF FLUOROQUINOLONE ANTIMICROBIALS BY PHAGOCYTES

吞噬细胞对氟喹诺酮类抗菌药物的摄取

• 批准号: 2592116
• 负责人: JOHN D WALTERS
• 金额: $ 11.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2592116
• 关键词: Actinobacillus actinomycetemcomitans; acidity /alkalinity; aerobiosis; aminoacid transport; anaerobiosis; antibacterial agents; antisense nucleic acid; body fluids; chemoattractants; cytokine; drug metabolism; enzyme activity; gingiva; human tissue; lipopolysaccharides; membrane transport proteins; mitogen activated protein kinase; monocyte; neutrophil; northern blottings; oligonucleotides; phagocytes; protein kinase C; sodium ion

DESCRIPTION (Adapted from investigator's Abstract): While polymorphonuclear leukocytes (PMNs) and mononuclear phagocytes are highly effective at clearing infections, several bacteria (including the periodontal pathogen Actinobacillus actinomycetemcomitans [A.a.]) can resist phagocytic killing. Antimicrobial therapy against intracellular pathogens is complicated by the inability of many agents to penetrate phagocytes. However, phagocytes take up ciprofloxcin and other fluoroquinolones with high affinity. When loaded with these bactericidal agents, PMNs exhibit enhanced phagocytic killing and can potentially serve as vehicles for fluoroquinolone delivery as they migrate from the bloodstream to infection sites (e.g., the periodontal pocket). Little is known of the mechanism by which phagocytes take up fluoroquinolones. Recent work from this laboratory indicates that PMN ciprofloxcin transport is a Na+-independent process that is competitively inhibited by cationic amino acids, properties known to be associated with amino acid transport system y+. Agents that activate protein kinase C (PKC) induce a dramatic increase in the Vmax of ciprofloxcin transport through a mechanism that appears to involve the mitogen-activated protein kinase (MAP kinase) cascade. This proposal will test the hypothesis that system y+ is the major mechanism for fluoroquinolone accumulation in phagocytes and is regulated by PKC and MAP kinase. The long-term objective is to enhance the effectiveness of antimicrobial therapy. Specific Aim 1 is to characterize and identify the transport system(s) by which PMNs and monocytes take up fluoroquinolones. Specific Aim 2 is to identify agents that stimulate fluoroquinolone transport in phagocytes and define the mechanisms by which this process is regulated, emphasizing the role of PKC and MAP kinase. Specific Aim 3 is to determine whether fluoroquinolone uptake by phagocytes contributes to enhanced delivery of fluoroquinolones to the periodontal pocket or enhanced killing of A.a.. Enhancement of phagocytic killing would be especially useful in the anaerobic environment of the pocket, where oxidative killing mechanism are ineffective. Ultimately, this work could facilitate new approaches for treating infections by A.a. and other pathogens that resist phagocytic killing (e.g., Salmonella and Chlamydia).

描述（改编自调查人员的摘要）：而多形核 白细胞（PMN）和单核吞噬细胞在 清除感染，几种细菌（包括牙周病原体 放线杆菌放线菌[A.A.]）可以抵抗吞噬细胞的杀戮。 针对细胞内病原体的抗菌治疗使 许多药物无法穿透吞噬细胞。 但是，吞噬细胞服用 提高环氧霉素和其他具有高亲和力的氟喹诺酮类药物。 加载时 使用这些杀菌剂，PMN表现出增强的吞噬性杀戮和 可以作为氟喹诺酮类传递的车辆 从血液迁移到感染部位（例如，牙周 口袋）。 关于吞噬细胞占用的机制知之甚少 氟喹诺酮。 该实验室的最新工作表明PMN 环氧霉素转运是一个Na+独立的过程，是竞争性的 被阳离子氨基酸抑制，已知与 氨基酸传输系统y+。 激活蛋白激酶C（PKC）的药物 诱导环霉素传输的Vmax通过A的VMAX急剧增加 似乎涉及有丝分裂原激活蛋白激酶的机制（MAP 激酶）级联。 该提案将检验以下假设：系统y+是 氟喹诺酮在吞噬细胞中积累的主要机制，IS 由PKC和MAP激酶调节。 长期目标是增强 抗菌治疗的有效性。 特定目标1是表征 并确定PMN和单核细胞占用的运输系统 氟喹诺酮。 特定目标2是确定刺激的代理 氟喹诺酮在吞噬细胞中的转运并定义了该机制 该过程受到调节，强调了PKC和MAP激酶的作用。 特定目标3是确定氟喹诺酮是否摄入吞噬细胞 有助于增强氟喹诺酮类为牙周的递送 口袋或增强杀害A.A ..增强吞噬性杀戮的能力将 在口袋的厌氧环境中特别有用 氧化杀伤机制无效。 最终，这项工作可能 促进A.A.治疗感染的新方法还有其他 抗吞噬细胞杀伤的病原体（例如沙门氏菌和衣原体）。