Bacterial Quorum Sensing as Target for Anti-Infective Immunotherapy

描述（由申请者提供）：最初发现革兰氏阴性细菌，如费氏弧菌和铜绿假单胞菌，利用小扩散分子，即n -酰基同丝氨酸内酯，来调节次生代谢物和蛋白质的产生，开创了微生物学研究的一个新领域，即群体感应领域。随后，其他群体感应系统和信号分子被确定，包括革兰氏阳性细菌中的寡肽，如金黄色葡萄球菌。群体感应系统似乎是进化保守的，其中许多系统都参与了细菌发病机制的控制。随着更多高抗生素耐药菌株（“超级细菌”）的出现，尤其是耐甲氧西林金黄色葡萄球菌（MRSA）和铜绿假单胞菌，迫切需要对抗细菌感染的新方法。事实上，美国疾病控制与预防中心（CDC）估计，2005年美国发生了94,000例侵袭性耐甲氧西林金黄色葡萄球菌感染，超过19,000名美国人死于这些感染——比每年艾滋病毒/艾滋病的死亡人数还要多。细菌群体感应信号分子可能是抗感染免疫治疗的新靶点。化学与分子生物学的有力结合将为群体猝灭治疗剂的研制提供坚实的理论基础。我们的R01应用的具体目标是：(1)基于ahl的群体感应在铜绿假单胞菌中的治疗靶向；(2)金黄色葡萄球菌agr群体感应系统作为免疫治疗靶点。公共卫生相关性：细菌性病原体，甚至是所谓的耐抗生素“超级细菌”，利用细胞间信号传导，一种称为“群体感应”的过程来控制其毒性。细菌用于交流的分子代表了抗感染治疗的有吸引力的目标，因为清除这些小化合物会使细菌无害。我们建议开发抗体并利用免疫系统来破坏细菌群体感应，从而成为对抗细菌感染的新策略。

DESCRIPTION (provided by applicant): The initial discovery that Gram-negative bacteria, such as Vibrio fischeri and Pseudomonas aeruginosa, employ small diffusible molecules, namely N-acyl homoserine lactones, to globally regulate the production of secondary metabolites and proteins, initiated a new area in microbiological research, the field of quorum sensing. Subsequently, other quorum sensing systems and signaling molecules have been identified, including oligopeptides in Gram-positive bacteria, such as Staphylococcus aureus. Quorum sensing systems seem to be evolutionary conserved and many of them are involved in the control of bacterial pathogenesis. With the emergence of more highly antibiotic-resistant bacterial strains ("superbugs"), most notably methicillin-resistant S. aureus (MRSA) and P. aeruginosa, new approaches for combating bacterial infections are desperately needed. In fact, the Center for Disease Control and Prevention (CDC) has estimated that 94,000 invasive MRSA infections occurred in the U.S in 2005 and more than 19,000 Americans died from these infections - more than annual HIV/AIDS casualties. Bacterial quorum sensing signaling molecules might represent such new targets for anti-infective immunotherapy. The powerful combination of chemistry and molecular biology will be harnessed to provide a solid rational basis for quorum quenching therapeutic agents. The specific aims of our R01 application are: (1) Therapeutic targeting of AHL-based Quorum Sensing in Pseudomonas aeruginosa; and (2) The agr Quorum Sensing System in Staphylococcus aureus as target for Immunotherapy. PUBLIC HEALTH RELEVANCE: Bacterial pathogens, even so-called antibiotic-resistant "super bugs", utilize cell-to-cell signaling, a process termed "quorum sensing", to control their virulence. The molecules that bacteria use for their communication represent attractive targets for anti-infective therapy as the scavenging of the small compounds would render the bacteria harmless. We propose to develop antibodies and harness the immune system in general for the disruption of bacterial quorum sensing and thus, a new strategy in fighting bacterial infections.