Pavlova Julia A, Khairullina Zimfira Z, Tereshchenkov Andrey G, Nazarov Pavel A, Lukianov Dmitrii A, Volynkina Inna A, Skvortsov Dmitry A, Makarov Gennady I, Abad Etna, Murayama Somay Y, Kajiwara Susumu, Paleskava Alena, Konevega Andrey L, Antonenko Yuri N, Lyakhovich Alex, Osterman Ilya A, Bogdanov Alexey A, Sumbatyan Natalia V
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, Russia.
A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119992 Moscow, Russia.
Antibiotics (Basel). 2021 Apr 23;10(5):489. doi: 10.3390/antibiotics10050489.
In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.
在当前工作中，作为我们近期研究的延续，我们合成并研究了新的嵌合化合物，其中包括靶向核糖体的抗生素氯霉素（CHL）和穿透细胞膜的阳离子三苯基膦（TPP），它们通过不同长度的烷基相连。通过各种生化分析，我们表明这些CAM-Cn-TPP化合物与细菌核糖体结合，在体外和体内以类似于母体CHL的方式抑制蛋白质合成，并显著降低膜电位。与CAM-C4-TPP类似，CAM-C10-TPP和CAM-C14-TPP在细菌核糖体中的作用方式与CHL不同。通过模拟CAM-Cn-TPP复合物与细菌核糖体的动力学，我们对这些类似物在翻译过程中作用的特异性提出了一种可能的解释。与CHL相比，CAM-C10-TPP和CAM-C14-TPP更强烈地抑制革兰氏阳性菌的生长，并抑制一些对CHL耐药的细菌菌株。因此，我们表明CHL的TPP衍生物是靶向细菌核糖体和细胞膜的双效化合物。CAM-Cn-TPP化合物的TPP片段对细菌有抑制作用。此外，由于真核细胞的线粒体具有与其原核祖先相似的特性，我们证明了用这些化合物靶向化疗耐药癌细胞的可能性。
