ИСТИНА

Antibiotic resistance is one of the biggest threats to human health, gaining momentum over the past decades. Therefore, the search and development of new antibacterial drugs is a prerequisite in order to turn the tide. Chloramphenicol is a widely used antibiotic that inhibits bacterial translation. Recent studies have shown that its activity depends on the sequence of the nascent chain carried by the ribosome. Replacement of the dichloroacetyl residue by positively charged groups in the chloramphenicol molecule changes its context-specificity and leads to an increase in the affinity for the ribosome. Berberine is an isoquinoline alkaloid, which also showed antibacterial effect as well as anti-inflammatory and antioxidant activity. The presence of a condensed system in the structure of the berberine molecule, by which a positive charge of a quaternary nitrogen atom is delocalized, makes this compound an excellent candidate for modification of chloramphenicol in order to enhance its affinity and eliminate context-specificity. The aim of this work was the design, synthesis and study of the antibacterial activity of berberine derivatives of chloramphenicol. Molecular docking of the proposed conjugates into the structure of the E. coli ribosome revealed additional stacking interactions between the berberine residue and the heterocyclic bases of 23S rRNA leading to an increase in binding affinity compared to the initial antibiotic. Based on the results obtained, a number of conjugates of berberine or its reduced analogue with chloramphenicol amine connected via linkers of different lengths were synthesized. The study of the binding of the obtained compounds to bacterial ribosomes showed a more than twofold increase in the affinity of some of them for the ribosome in comparison with chloramphenicol. Evaluation of antibacterial activity using the pDualrep2 double reporter system [1] revealed that the action of the synthesized compounds is caused by both ribosome stalling due to interactions with rRNA nucleotides and DNA damage. This work was supported by the grant RFBR 20-04-00873А.