Bacterial-Ribosome-Structure based Approaches for the Development of Novel Antimicrobial Agents

Sivan Louzoun, School of Chemistry, Tel Aviv University, Tel Aviv, Israel
Keith D. Green, Sylvie Garneau-Tsodikova, Department of Medicinal Chemistry and the Life Sciences Institute, University of Kentucky Lexington
Micha Fridman, School of Chemistry, Tel Aviv University, Tel Aviv, Israel

Antibiotics are powerful medicines that fight bacterial infections. However, the extent of antibiotics resistance has led chemists to explore numerous strategies to regain efficacy to antimicrobial agents. In the vast majority of cases, these strategies did not result with improved biological performance. The main reason for the low success rate stems from the fact that drug designers have to cope, among others, with the lack of detailed structure-based information that will assist them in molecular design of novel antibiotics. In this study we aim to develop new types of prokaryotic protein synthesis Inhibitors, based on the solved structure of the bacterial ribosome segments and their complexes with several antibiotics. The target antibiotic in our study is chloramphenicol (CAM).

CAM binds specifically to nucleotides of the 23S rRNA and prevents peptide bond formation. X-ray crystallography of CAM bound to the 50s subunit of E. coli ribosomes offered insights of the chemical functionalities that form significant interactions with the target 23s rRNA. Based on structural data we synthesized a collection of novel CAM derivatives. Some of the compounds were prepared by modification of the dichloroacetamide part of CAM since the two chlorine atoms of this chemical group appear to have no significant role in target binding. Other derivatives were designed by modifying the primary-OH and secondary-OH to groups that will facilitate binding to the ribosome via novel hydrogen bonds. Moreover, the synthetic CAM derivatives were designed to evade the activity of CAM deactivating enzymes that evolved in bacteria to confer resistance to the parent antibiotic. Antimicrobial activity tests, ribosome inhibition properties, and the ability to evade deactivation through CAM modifying enzymes were explored and are discussed.