School of Chemistry, Tel Aviv University , Tel Aviv, 6997801, Israel.
J Med Chem. 2013 Jul 11;56(13):5613-25. doi: 10.1021/jm400707f. Epub 2013 Jul 1.
In this study, we describe the synthesis of a full set of homo- and heterodimers 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.
在这项研究中，我们描述了一整套三种不同核糖体靶向抗生素的完整同型和异型二聚体的合成：妥布霉素、克林霉素和氯霉素。评估了二聚体结构的几个方面的生物活性，包括抗菌活性、抑制体外细菌蛋白质翻译以及二聚化对几种使妥布霉素和氯霉素失活的细菌耐药机制的作用。这项研究表明，将两种相同或不同的核糖体靶向抗生素共价连接可能导致 (i) 抗菌活性谱更广，(ii) 与母体抗生素相比，对细菌翻译特性的抑制作用得到改善，以及 (iii) 降低一些修饰酶的功效，这些酶使母体抗生素产生高水平的耐药性，而这些二聚体则来自母体抗生素。
