Bacterial Quorum Sensing as Target for Anti-Infective Immunotherapy

描述(申请人提供)：最初发现革兰氏阴性菌，如费氏弧菌和铜绿假单胞菌，利用小的可扩散分子，即N-酰基高丝氨酸内酯，来全球调节次级代谢物和蛋白质的生产，这开启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也被鉴定出来，包括革兰氏阳性细菌中的寡肽，如金黄色葡萄球菌。群体感应系统似乎在进化上是保守的，其中许多系统参与了细菌发病的控制。随着更多高度耐药的细菌菌株(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，迫切需要新的方法来对抗细菌感染。事实上，疾病控制和预防中心(CDC)估计，2005年美国发生了94,000例侵袭性MRSA感染，超过19,000名美国人死于这些感染--超过每年艾滋病毒/艾滋病的死亡人数。细菌群体感应信号分子可能是抗感染免疫治疗的新靶点。化学和分子生物学的强大结合将为群体猝灭治疗药物提供坚实的合理基础。我们R01应用的具体目标是：(1)以AHL为基础的铜绿假单胞菌群体感应的治疗靶点；(2)金黄色葡萄球菌的AGR群体感应系统作为免疫治疗的靶点。与公共卫生相关：细菌病原体，甚至是所谓的抗药性“超级细菌”，利用细胞间信号传递，一种被称为“群体感应”的过程，来控制它们的毒力。细菌用于交流的分子是抗感染治疗的有吸引力的目标，因为清除小化合物将使细菌无害。我们建议开发抗体并利用免疫系统来破坏细菌群体感应，从而为对抗细菌感染提供一种新的策略。

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.