Tackling antibiotic resistance by targeting toxin antitoxin system – TARTAS

The emergence of antibiotic resistance poses global health and economical threats. To maintain efficient therapies against bacterial infections and prevent the spread of antibiotic resistance, it is urgent to design new antimicrobials. Taking advantage of intrinsic bacterial death systems such as Toxin-Antitoxin (TA) systems would constitute a unique opportunity to design smart antibiotics. This project focuses on type I TA (T1TA) systems where RNA antitoxins prevent the translation of complementary toxin coding mRNAs. These systems have been identified in two major bacterial pathogens considered as urgent threats in antibiotic resistance, Helicobacter pylori and Clostridioides difficile. The main goal of the TARTAS project is to characterize RNA-regulated T1TA systems encoded on the chromosome, in order to be able to use them as “genome encoded” antibiotics. To this aim, we will combine genetic and biochemical approaches coupled with high-throughput sequencing in these two human pathogenic bacteria to i) analyze the killing capacity of chromosomal T1TA systems, ii) decipher the regulation of toxin mRNA expression, iii) investigate the molecular mechanism used by the antitoxin RNA to repress the toxin expression and finally, iv) activate toxin expression by targeting antitoxin RNA with antisense oligonucleotides. Successful completion of this project will not only shed light on the critical aspects of T1TA regulatory mechanisms, but could also reveal RNA antitoxins as new potent antibacterial targets.