Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis.
Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis.
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DOI：
10.1016/j.chom.2011.09.010
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发表时间：
2011-11-17
影响因子：
30.3
通讯作者：
Kalman D
中科院分区：
文献类型：
--
作者：
Napier RJ;Rafi W;Cheruvu M;Powell KR;Zaunbrecher MA;Bornmann W;Salgame P;Shinnick TM;Kalman D
目前使用的抗分枝杆菌药物的疗程较长，以及由此产生的耐药菌株，加剧了对针对结核病病原体——结核分枝杆菌 (Mtb) 的替代疗法的需求。我们发现 Mtb 和海分枝杆菌使用 Abl 和相关酪氨酸激酶进入巨噬细胞并在细胞内存活。在小鼠中，Abl 家族酪氨酸激酶抑制剂伊马替尼 (Gleevec®) 在预防性或治疗性给药时，可减少受感染器官中的肉芽肿病变数量和细菌载量，并且对利福平耐药菌株也有效。此外，当与目前的一线药物利福平或利福布汀共同给药时，伊马替尼具有协同作用。这些数据表明宿主酪氨酸激酶参与分枝杆菌的进入和细胞内存活，并表明伊马替尼可能对结核分枝杆菌具有治疗功效。由于伊马替尼针对宿主，与传统抗生素相比，它不太可能产生耐药性，并且可能会减少对联合用药的耐药性的发展。
The lengthy course of treatment with currently used anti-mycobacterial drugs and the resulting emergence of drug-resistant strains have intensified the need for alternative therapies against Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. We show that Mtb and Mycobacterium marinum use Abl and related tyrosine kinases for entry and intracellular survival in macrophages. In mice, the Abl-family tyrosine kinase inhibitor, imatinib (Gleevec®), when administered prophylactically or therapeutically, reduced both the number of granulomatous lesions and bacterial load in infected organs, and was also effective against a rifampicin-resistant strain. Further, when co-administered with current first-line drugs, rifampicin or rifabutin, imatinib acted synergistically. These data implicate host tyrosine kinases in entry and intracellular survival of mycobacteria, and suggest that imatinib may have therapeutic efficacy against Mtb. Because imatinib targets host, it is less likely to engender resistance compared to conventional antibiotics, and may decrease the development of resistance against co-administered drugs.
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