Predicting the Mode of Action of Anti-Bacterial Effector Domains in Type VI Secretion System-Delivered Rhs Proteins

Abstract

Serratia marcescens is an opportunistic Gram-negative bacterium that has been linked to hospital-acquired infections and has shown antibiotic resistance. This bacterium possesses a Type VI secretion system (T6SS) that is vital for its survival as it is used to target competing bacterial species. T6SS also enhances bacterial virulence by aiding in colonization, evading immune responses, and damaging host cells. The T6SS secretes a range of effector proteins, which are known to possess functionalities like nuclease, ADP-ribosyl transferase, deaminase, phospholipase, and hydrolases. The bacteria protect themselves from these toxins by secreting immunity proteins that bind to and neutralize the effector proteins. S. marcescens contains a highly specialized class of T6SS Rhs toxins whose CT domains are highly variable. As a result, it is difficult to determine the function of these toxin domains. In our current study, we have investigated the function of a set of CTs belonging to Rhs effectors using structure prediction and comparative structural homology studies. In our study, these CTs were found to possess activities like ribonucleases, endonucleases, deaminases, and ADP-ribosyl transferases. Additionally, we found that some toxins can also act as inhibitors for important enzymes, such as Uracil DNA glycosylase, transposase, nuclease, etc. We also tried predicting the possible mechanisms by which the immunity proteins can neutralize the toxins. By performing these studies, we can understand the mechanism and target of these toxins which can effectively be used to design antimicrobials for specific pathogens.