(R)-Roscovitine and CFTR modulators enhance killing of multi-drug resistant Burkholderia cenocepacia by cystic fibrosis macrophages.
(R)-Roscovitine and CFTR modulators enhance killing of multi-drug resistant Burkholderia cenocepacia by cystic fibrosis macrophages.
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DOI：
10.1038/s41598-020-78817-x
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发表时间：
2020-12-10
影响因子：
4.6
通讯作者：
Kopp BT
中科院分区：
文献类型：
--
作者：
Shrestha CL;Zhang S;Wisniewski B;Häfner S;Elie J;Meijer L;Kopp BT
囊性纤维化（CF）的特点是慢性细菌感染和炎症加剧。抗生素的广泛无效使用导致从呼吸道样本中分离出更多的耐药菌株。 (R)-roscovitine (Seliciclib) 是一种独特的药物，在 CF 研究中具有许多益处。我们试图确定罗可维汀对巨噬细胞功能和杀死多重耐药细菌的影响。从 CF (F508del/F508del) 和非 CF 人群中分离人血单核细胞，并衍生为巨噬细胞 (MDM)。 MDM 感染了 Cenocepacia 和 P. aeruginosa 的 CF 临床分离株。 MDMs 用 (R)-roscovitine 或其主要肝脏代谢物 (M3) 治疗。确定巨噬细胞对感染和后续治疗的反应。 (R)-roscovitine 和 M3 以剂量依赖性方式显着增加 CF MDM 中对新洋葱伯克霍尔德杆菌和铜绿假单胞菌的杀灭作用。 (R)-roscovitine 介导的作用部分依赖于 CFTR 和 TRPC6 通道。通过与 CFTR 调节剂 tezacaftor/ivacaftor 和/或替代 CFTR 调节剂半胱胺联合使用，(R)-roscovitine 介导的对新洋葱伯克虫的杀灭作用得到增强。与单独使用 tezacaftor/ivacaftor 治疗相比，(R)-roscovitine 还增加了 MDM CFTR 功能。 (R)-roscovitine 可增加 CF 巨噬细胞介导的对抗生素耐药细菌的杀灭作用。 (R)-roscovitine 还增强其他巨噬细胞功能，包括 CFTR 介导的离子流出。 (R)-roscovitine 与 CFTR 调节剂或半胱胺联合使用时效果最佳，这证明了 (R)-roscovitine 或优化衍生物的进一步临床测试是合理的。
Cystic fibrosis (CF) is characterized by chronic bacterial infections and heightened inflammation. Widespread ineffective antibiotic use has led to increased isolation of drug resistant bacterial strains from respiratory samples. (R)-roscovitine (Seliciclib) is a unique drug that has many benefits in CF studies. We sought to determine roscovitine’s impact on macrophage function and killing of multi-drug resistant bacteria. Human blood monocytes were isolated from CF (F508del/F508del) and non-CF persons and derived into macrophages (MDMs). MDMs were infected with CF clinical isolates of B. cenocepacia and P. aeruginosa. MDMs were treated with (R)-roscovitine or its main hepatic metabolite (M3). Macrophage responses to infection and subsequent treatment were determined. (R)-roscovitine and M3 significantly increased killing of B. cenocepacia and P. aeruginosa in CF MDMs in a dose-dependent manner. (R)-roscovitine-mediated effects were partially dependent on CFTR and the TRPC6 channel. (R)-roscovitine-mediated killing of B. cenocepacia was enhanced by combination with the CFTR modulator tezacaftor/ivacaftor and/or the alternative CFTR modulator cysteamine. (R)-roscovitine also increased MDM CFTR function compared to tezacaftor/ivacaftor treatment alone. (R)-roscovitine increases CF macrophage-mediated killing of antibiotic-resistant bacteria. (R)-roscovitine also enhances other macrophage functions including CFTR-mediated ion efflux. Effects of (R)-roscovitine are greatest when combined with CFTR modulators or cysteamine, justifying further clinical testing of (R)-roscovitine or optimized derivatives.
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
3.7
作者：
Shrestha CL;Assani KD;Rinehardt H;Albastroiu F;Zhang S;Shell R;Amer AO;Schlesinger LS;Kopp BT
通讯作者：
Kopp BT
DOI：
10.1016/j.bbrc.2012.06.066
发表时间：
2012-07-27
影响因子：
3.1
作者：
Kopp, Benjamin T.;Abdulrahman, Basant A.;Amer, Amal O.
通讯作者：
Amer, Amal O.
影响因子：
4.9
作者：
Lucero, Cynthia A.;Cohen, Adam L.;Srinivasan, Arjun
通讯作者：
Srinivasan, Arjun
影响因子：
4.6
作者：
Zhang, Shuzhong;Shrestha, Chandra L.;Kopp, Benjamin T.
通讯作者：
Kopp, Benjamin T.