抗疟药物靶向 DosRS 信号通路在 …… 中的治疗效果。
Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in .
机构信息
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
出版信息
Sci Transl Med. 2022 Feb 23;14(633):eabj3860. doi: 10.1126/scitranslmed.abj3860.
A search for alternative treatments led to our interest in the two-component regulator DosRS, which, in , is required for the bacterium to establish a state of nonreplicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of impairs the adaptation of to hypoxia, resulting in decreased bacterial survival after oxygen depletion, reduced tolerance to a number of antibiotics in vitro and in vivo, and the inhibition of biofilm formation. We determined that three antimalarial drugs or drug candidates, artemisinin, OZ277, and OZ439, can target DosS-mediated hypoxic signaling in and recapitulate the phenotypic effects of genetically disrupting . OZ439 displayed bactericidal activity comparable to standard-of-care antibiotics in chronically infected mice, in addition to potentiating the activity of antibiotics used in combination. The identification of antimalarial drugs as potent inhibitors and adjunct inhibitors of in vivo offers repurposing opportunities that could have an immediate impact in the clinic.
我们寻找替代疗法，引起了我们对双组分调控因子 DosRS 的关注。在 中，该因子是细菌在应对多种宿主应激时建立非复制、耐药性持久状态所必需的。我们在这里表明， 基因的破坏会损害 对低氧的适应，导致缺氧耗尽后细菌存活率降低，体外和体内对多种抗生素的耐受性降低，以及生物膜形成的抑制。我们确定三种抗疟药物或药物候选物，青蒿素、OZ277 和 OZ439，可以靶向 DosS 介导的 中的低氧信号，并重现遗传破坏的表型效应。OZ439 在慢性感染的小鼠中显示出与标准护理抗生素相当的杀菌活性，此外还增强了联合使用的抗生素的活性。抗疟药物作为体内 强有力的抑制剂和辅助抑制剂的鉴定提供了重新利用的机会，这可能会对临床产生直接影响。
Zotero 插件