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

 描述(申请人提供)：在重要的人类病原体金黄色葡萄球菌中，SaeRS双组分系统(TCS)对于产生多种毒力因子和提高细菌在宿主中的生存至关重要。在这项应用中，将探索一种新的方法，通过靶向SaeRS TCS来开发抗葡萄球菌药物。虽然常规抗生素直接杀死细菌，并存在耐药性问题，但新型抗葡萄球菌制剂只会降低细菌的致病潜能，而不会杀死细菌；因此，该制剂有望补充传统抗生素方案，而不会出现耐药性问题。在R21阶段，我们将确定两个有效的SAE-抑制剂的领先候选者。在目标1中，将通过筛选8万个小分子来鉴定有希望的热门化合物。已确定的命中化合物将进一步检测它们对人类细胞系的毒性。目标2，通过药代动力学试验，筛选出代谢稳定性好、体内毒性低的HIT化合物。在目标3中，选定的化合物将在小鼠感染模型中进一步检验它们的体内有效性；两个主要候选化合物将 已确定用于R33阶段研究。只有当两位主要候选人达到R21里程碑时，才会开始R33阶段。在R33阶段，这两个主要候选药物将得到进一步改进，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，将生成候选先导化合物的衍生物；然后通过药效和稳定性试验来鉴定具有改进药理特性的衍生物。在人工智能2中，将检查主要候选者在治疗过程中与传统抗生素的协同作用 葡萄球菌感染。在目标3中，将通过鉴定候选铅的直接结合靶标和分离抗性突变体来确定候选铅抑制SaeRS TCS的机制。最后，在目标4中，将彻底检查候选铅在类似临床环境的情况下是否有可能导致耐药突变的出现。这项研究的总体目标是确定SaeRS TCS的抑制剂是否可以作为一种新型的抗金黄色葡萄球菌药物来对抗金黄色葡萄球菌的耐药性问题。

 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.