Paul G. Allen School for Global Health, Washington State University, Pullman, Washington 99164, United States.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
ACS Infect Dis. 2024 Aug 9;10(8):2775-2784. doi: 10.1021/acsinfecdis.4c00116. Epub 2024 Jun 14.
is a Gram-negative facultative intracellular bacterial pathogen that is classified by the Centers for Disease Control and Prevention as a Tier 1 Select Agent. infection causes the disease tularemia, also known as rabbit fever. Treatment of tularemia is limited to few effective antibiotics which are associated with high relapse rates, toxicity, and potential emergence of antibiotic-resistant strains. Consequently, new therapeutic options for tularemia are needed. Through screening a focused chemical library and subsequent structure-activity relationship studies, we have discovered a new and potent inhibitor of intracellular growth of , D8-03. Importantly, D8-03 effectively reduces bacterial burden in mice infected with . Preliminary mechanistic investigations suggest that D8-03 works through a potentially novel host-dependent mechanism and serves as a promising lead compound for further development.
是一种革兰氏阴性兼性细胞内细菌病原体，被疾病控制与预防中心列为 1 级选择剂。感染会导致土拉热，也称为野兔热。土拉热的治疗方法有限，只有少数几种有效的抗生素，但这些抗生素与高复发率、毒性和潜在的抗生素耐药菌株的出现有关。因此，需要新的土拉热治疗方法。通过筛选一个有针对性的化学文库，并进行后续的结构-活性关系研究，我们发现了一种新的、有效的抑制细胞内生长的抑制剂，D8-03。重要的是，D8-03 能有效降低感染的小鼠中的细菌负荷。初步的机制研究表明，D8-03 通过一种潜在的新型宿主依赖性机制发挥作用，是进一步开发的有前途的先导化合物。
