Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: antimicrobial activity, in vitro inhibition of translation, and drug resistance.
Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: antimicrobial activity, in vitro inhibition of translation, and drug resistance.
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DOI：
10.1021/jm400707f
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发表时间：
2013-07-11
影响因子：
7.3
通讯作者：
Fridman M
中科院分区：
文献类型：
--
作者：
Berkov-Zrihen Y;Green KD;Labby KJ;Feldman M;Garneau-Tsodikova S;Fridman M
在这项研究中，我们描述了一套完整的同源和异源二聚体的三个完整结构的不同核糖体靶向抗生素：妥布霉素，克林霉素，氯霉素的合成。评价了二聚体结构的生物活性的几个方面，包括抗微生物活性、体外细菌蛋白质翻译的抑制以及二聚化对使妥布霉素和氯霉素失活的几种细菌抗性机制的作用的影响。这项研究表明，共价连接两种相同或不同的核糖体靶向抗生素可能导致（i）更广谱的抗微生物活性，（ii）与母体抗生素相比，改善对细菌翻译特性的抑制，以及（iii）降低某些药物修饰酶的功效，这些药物修饰酶对衍生二聚体的母体抗生素具有高水平的耐药性。
In this study, we describe the synthesis of a full set of homo- and hetero-dimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived.
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DOI：
10.1016/j.bbapap.2008.11.005
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Delcour AH
通讯作者：
Delcour AH
影响因子：
2.7
作者：
Hubschwerlen, C;Specklin, JL;Locher, HH
通讯作者：
Locher, HH
影响因子：
64.5
作者：
Brodersen, DE;Clemons, WM;Ramakrishnan, V
通讯作者：
Ramakrishnan, V
影响因子：
5.6
作者：
Hansen, JL;Moore, PB;Steitz, TA
通讯作者：
Steitz, TA
影响因子：
8
作者：
Biswas, Tapan;Houghton, Jacob L.;Tsodikov, Oleg V.
通讯作者：
Tsodikov, Oleg V.