Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus.
Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus.
复制标题
针对DosRS信号通路的抗疟疾药物对脓肿分枝杆菌的疗效。
DOI：
10.1126/scitranslmed.abj3860
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发表时间：
2022-02-23
影响因子：
17.1
通讯作者：
Jackson M
中科院分区：
文献类型：
--
作者：
Belardinelli JM;Verma D;Li W;Avanzi C;Wiersma CJ;Williams JT;Johnson BK;Zimmerman M;Whittel N;Angala B;Wang H;Jones V;Dartois V;de Moura VCN;Gonzalez-Juarrero M;Pearce C;Schenkel AR;Malcolm KC;Nick JA;Charman SA;Wells TNC;Podell BK;Vennerstrom JL;Ordway DJ;Abramovitch RB;Jackson M
寻找替代的结核分枝杆菌治疗导致了我们对双组分调节剂DosRS的兴趣，该调节剂在结核分枝杆菌中是细菌建立响应于各种宿主应激的非复制、耐药持久性状态所需的。我们在这里表明，dosRS的遗传破坏损害的适应M。缺氧，导致氧气耗尽后细菌存活率降低，体外和体内对许多抗生素的耐受性降低，以及生物膜形成的抑制。我们确定了三种抗疟药物或候选药物，青蒿素，OZ277和OZ439，可以靶向M.概括和概括遗传破坏剂量的表型效应。重要的是，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M.体内的Spectuessus提供了重新利用的机会，可能会在临床上产生直接的影响。抗疟药的再利用以治疗肺部非结核分枝杆菌感染。
A search for alternative Mycobacterium abscessus treatments led to our interest in the two-component regulator DosRS which, in Mycobacterium tuberculosis, is required for the bacterium to establish a state of non-replicating, drug-tolerant persistence in response to a variety of host stresses. We show here that the genetic disruption of dosRS impairs the adaptation of M. abscessus to hypoxia, resulting in decreased bacterial survival following 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 M. abscessus and recapitulate the phenotypic effects of genetically disrupting dosS. Importantly, 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 M. abscessus in vivo offers repurposing opportunities that could have an immediate impact in the clinic. Repurposing of antimalarial drugs to treat pulmonary nontuberculous mycobacterial infections.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
3.1
作者：
Holland, SM
通讯作者：
Holland, SM
DOI：
10.1165/rcmb.2016-0239oc
发表时间：
2017-05-01
影响因子：
6.4
作者：
Hudock, Teresa A.;Foreman, Taylor W.;Kaushal, Deepak
通讯作者：
Kaushal, Deepak
DOI：
10.1165/rcmb.2014-0230oc
发表时间：
2015-06-01
影响因子：
6.4
作者：
Gautam, Uma S.;McGillivray, Amanda;Kaushal, Deepak
通讯作者：
Kaushal, Deepak
影响因子：
4.9
作者：
Chuang, Yu-Min;Dutta, Noton K.;Karakousis, Petros C.
通讯作者：
Karakousis, Petros C.