Protein synthesis inhibition by underrepresented sequences: a new class of novel ribosomal antibiotics

Abstract

Bacteria and other pathogenic organisms have always evolved so that they can resist harmful compounds – including the drugs that medicine has used to combat them. Antimicrobial Resistance has increasingly become a serious problem in recent years because the pace at which we are discovering novel antibiotics has slowed drastically, due to the tremendous costs which required for antibiotics innovation, and while classic antibiotics use is rising, the bacteria become more resistant to these compounds, therefore the efficiency of bacterial infection therapy has dropped, responsible for the death of hundreds of thousands of people annually. However, cell proteomic analyses by a Bioinformatics method which we called Underrepresented Sequences, able to detect short peptide sequences which are rarely present or totally excluded from the cell (for short we call them URS’s). Previous study of our lab examined the URS’s presence effect in vivo, by genetically modified BL 21 E. coli able to express protein with embedded URS sequences, and we observed that when the URS-protein was expressed, ribosomal activity was significantly reduced, leading to protein synthesis inhibition, followed by cell damage or death (Navon, Sharon Penias, et al). The study determined that the URS inhibitory action results from interfering with the ribosome exit tunnel, leading to ribosomal stalling.

Navon, Sharon Penias, et al. "Amino acid sequence repertoire of the bacterial proteome and the occurrence of untranslatable sequences." Proceedings of the National Academy of Sciences113.26 (2016): 7166-7170.‏