Toxic small RNAs that regulate essential genes in Salmonella, a combined experimental and computational approach

• Applicant: Dr. Jens Georg
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423781197

Bacterial small regulatory RNAs (sRNAs) are key players in many adaptive responses. Typically, sRNAs allow bacterial cells to adapt to changing environmental conditions by the post-transcriptional regulation of distinct genes that are directly linked to the specific stress or condition. In contrast, the present project aims at the investigation of the insufficiently characterized class of sRNAs for which high levels of expression are, at first glance, detrimental. We propose that besides general regulatory functions, the class of detrimental sRNAs is able to cause e.g. dormancy or persistence, which eventually helps the cell to cope with diverse stress conditions. An example is the OxyS sRNA, which upon oxidative stress, indirectly and transiently inhibits cell division to enhance survival and to reduce the mutation rate. In this study, we expect to define new regulatory concepts of steered self-toxicity, where sRNAs repress essential genes involved in e.g. cell division, translation, replication and LPS synthesis or activate toxic proteins, to provide a significant situational fitness advantage. Besides, the functional characterization of detrimental sRNAs we are also interested in the evolution of sRNAs and their regulons. Some (detrimental) sRNAs are widely conserved within the Enterobacteriaceae, but due to shifting target sets, toxicity is likely restricted to individual species. We will investigate the evolutionary driving force, which brought about the development of (transiently) toxic sRNAs (trans-toxic sRNAs) in Salmonella or related (sub)-species to gain insight into bacterial adaptions to different lifestyles or host preferences. This project requires the large scale analysis of a high number of potential sRNAs and is thus the perfect use case to apply and improve the computational tools for sRNA target prediction and (evolutionary) analysis.Understanding of so far unknown mechanisms, by which regulation of essential genes through sRNAs results in bacterial growth arrest, may lead to a better understanding of Salmonella virulence. The increase in the number of resistant bacteria including “superbugs” is a real threat on our ability to cope with infectious diseases, while the world of antimicrobial drugs is currently limited to the common, overused antibiotic compounds. We expect the characterization of trans-toxic sRNAs with their targets to enrich and renew the repertoire of drug targets and thus develop new opportunities to eliminate pathogenic bacteria. Furthermore, we will develop and provide new powerful and easy-to-use leading edge computational tools for the analysis of bacterial sRNAs to the scientific community.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Shoshy Altuvia, Ph.D.