Development of anti-virulence drugs by targeting the SaeRS two component system of Staphylococcus aureus

 描述（由申请方提供）：在金黄色葡萄球菌（一种重要的人类病原体）中，SaeRS双组分系统（TCS）对于产生多种毒力因子和增强细菌在宿主中的存活至关重要。在本申请中，将探索通过靶向SaeRS TCS开发抗葡萄球菌药物的新方法。尽管传统抗生素直接杀死细菌并遭受耐药性问题，但新的抗葡萄球菌剂仅会降低细菌的致病潜力而不会杀死细菌;因此，该剂有望补充传统抗生素方案而不会产生耐药性问题。 在R21阶段，我们将鉴定Sae抑制剂的两种有效的先导候选物。在目标1中，将通过筛选80，000个小分子来鉴定有希望的命中化合物。将进一步检查鉴定的命中化合物对人类细胞系的毒性。目标二是通过药代动力学试验，筛选出代谢稳定性好、体内毒性低的目标化合物。在目标3中，将进一步检查所选化合物在小鼠感染模型中的体内功效;并将研究两种主要候选化合物 在R33阶段研究中确定。只有当两个主要候选人满足R21里程碑时，才会进行R33阶段。 在R33阶段，这两种主要候选药物将进一步改进，同时将彻底检查它们作为新型抗葡萄球菌药物的潜力。在目标1中，将生成先导候选物的衍生物;然后将通过功效和稳定性测试来鉴定具有改善的药理学特性的衍生物。在Ai 2中，将检查主要候选药物与常规抗生素在治疗中的协同作用。 葡萄球菌感染在目标3中，将通过鉴定先导候选物的直接结合靶标并分离抗性突变体来确定先导候选物抑制SaeRS TCS的机制。最后，在目标4中，将彻底检查主要候选药物在类似于临床环境的条件下导致耐药突变体出现的潜力。 本研究的总体目标是确定SaeRS TCS的抑制剂是否可以成为一种新型的抗葡萄球菌药物，用于对抗葡萄球菌的抗生素耐药性问题。金黄色。

 DESCRIPTION (provided by applicant): In Staphylococcus aureus, an important human pathogen, the SaeRS two component system (TCS) is essential for producing multiple virulence factors and enhancing the bacterium's survival in the host. In this application, a novel approach will be explored to develop anti-staphylococcal drugs by targeting the SaeRS TCS. Although conventional antibiotics directly kill bacteria and suffer from resistance problems, the new anti-staphylococcal agent will reduce only the pathogenic potential of the bacterium without killing; therefore, the agent is expected to complement the conventional antibiotics regimen without a resistance problem. In the R21 phase, we will identify potent two lead candidates of the Sae-inhibitor. In Aim 1, promising hit compounds will be identified by screening 80,000 small molecules. The identified hit compounds will be further examined for their toxicity on a human cell line. In Aim 2, through pharmacokinetic tests, the hit compounds with good metabolic stability and low in vivo toxicity will be selected. In Aim 3, the selected compounds will be furthr examined for their in vivo efficacy in a murine model of infection; and two lead candidates will be identified for the R33 phase study. Only when the two lead candidates satisfy the R21 milestones, will the R33 phase be undertaken. In the R33 phase, the two lead candidates will be further improved, while their potential as a novel anti- staphylococcal drug will be thoroughly examined. In Aim 1, derivatives of the lead candidates will be generated; then the derivatives with improved pharmacological traits will be identified through efficacy and stability tests. In Ai 2, the lead candidates will be examined for their synergy with conventional antibiotics in treating staphylococcal infections. In Aim 3, the mechanism by which the lead candidates inhibit the SaeRS TCS will be determined by identifying the direct binding targets of the lead candidates and isolating resistant mutants. Finally, in Aim 4, the lead candidates will be thoroughly examined for their potential to cause emergence of resistant mutants in a condition similar to clinical settings. The overall goal of this study is to determine whether the inhibitors of the SaeRS TCS can be a novel anti-staphylococcal drug in combating the antibiotic resistance problem of S. aureus.