Small Molecule Inhibitors of P. aeruginosa Quinolone (Pqs) Quorum Sensing

描述（由申请人提供）：铜绿假单胞菌是一种机会性革兰氏阴性病原体，在医院感染的背景下对公共卫生构成重大威胁，特别是对免疫功能低下的患者，如烧伤患者、癌症患者、囊性纤维化或艾滋病患者。铜绿假单胞菌也容易通过内在和获得性机制产生抗生素耐药性。因此，迫切需要开发新的抗假单胞菌药物，以解决未开发的靶点，这是本RFA的一个特别重点。为了解决这一问题，我们建议开发针对P. aeruginosa quinolone （Pqs）群体感应系统的新型小分子抗菌药物。这是小鼠感染模型中药理学验证的靶标，不同于酰基高丝氨酸内酯（Las, Rhl）群体感应系统。喹诺酮类药物是由细菌生物合成的小分子，用于细胞-细胞信号传导。它们控制多种细菌毒力因子基因的表达，这些基因与致病性相关，但不是

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that poses a significant public health threat in the context of nosocomial infections, particularly for immunocompromised patients such as burn victims, cancer patients, and individuals having cystic fibrosis or AIDS. P. aeruginosa is also prone to antibiotic resistance, through both intrinsic and acquired mechanisms. Thus, there is a great need for the development of novel anti-Pseudomonas drugs that address unexploited targets, and this is a specific focus of this RFA. To address this problem, we propose herein to develop novel small molecule antibacterials that target the P. aeruginosa quinolone (Pqs) quorum sensing system. This is a pharmacologically validated target in a mouse model of infection and is distinct from acyl homoserine lactone (Las, Rhl) quorum sensing systems. Quinolones are small molecules that are biosynthesized by the bacteria and used in cell-cell signaling. They control expression of a variety of bacterial virulence factor genes that are associated with pathogenicity but are not required for bacterial viability or growth. As such, novel antibacterials that target such virulenc factors are thought less likely to elicit drug resistance compared to traditional bacteriotoxic and bacteriostatic antibiotics. Building upon extensive previous work from the three participating laboratories (Tan, Rahme, Pesci), we will use mechanism- and structure-based rational drug design to develop small molecule inhibitors of PqsA, an anthraniloyl-CoA synthetase that catalyzes an essential step in P. aeruginosa quinolone biosynthesis. PqsA has been validated as an effective antibacterial target in a mouse model using simple substrate analogues, but more potent and specific inhibitors are required to exploit fully the therapeutic potential of this target. In the R21 phase, we will synthesize first-generation inhibitors using a rational design strategy that has been applied successfully to related targets in the Tan lab, then evaluate their activities in biochemical and cellular assays for PqsA activity and quinolone production established previously in the Pesci and Rahme labs. In the R33 phase, we will optimize the biochemical, cellular, and pharmacological properties of the inhibitors to develop lead compounds that will then be advanced to in vivo evaluation in established mouse models of P. aeruginosa infection in the Rahme lab. This multidisciplinary collaboration comprises the necessary combined expertise in synthetic organic chemistry, medicinal chemistry, biochemistry, pharmacology, and microbiology. Our long- term goals are to develop one or more advanced candidates for further preclinical and clinical evaluation as novel antibiotics to combat P. aeruginosa and potentially other pathogenic Gram-negative bacteria. PUBLIC HEALTH RELEVANCE: Pseudomonas aeruginosa is a pathogenic bacteria that poses a significant public health threat to hospitalized, immunocompromised patients such as burn victims, cancer patients, and individuals having cystic fibrosis or AIDS. The goal of this project is to develop novel antibacterial drugs to combat P. aeruginosa infections by targeting a bacterial process called quorum sensing, which is associated with virulence and pathogenicity and may be less prone to eliciting antibacterial resistance.