Like an assassin sneaking up behind its target and administering a lethal injection before disappearing back into the crowd, some bacteria are known to produce and inject toxins into competing host or bacterial cells to kill them.
ADP-ribosyltransferases (ARTs) are a family of structurally related proteins that inactivate cellular processes and promote cell death. Among the first ART to be identified was diphtheria toxin.
Diphtheria is caused by the bacteria Corynebacterium diphtheriae. However, it is the toxins produced by the bacteria, rather than the bacteria themselves, that primarily cause symptoms. The same is true of tetanus and pertussis.
Now, biologists have discovered a previously unknown ART toxin produced by the bacterial pathogen Pseudomonas aeruginosa – known to cause hospital-acquired infections such as pneumonia – that specifically targets RNA instead of proteins.
This discovery breaks well-established precedents set by ARTs that only target proteins.
The findings of a recent study reported in the journal Molecular Cell, could help pave the way for new types of antibiotics to help combat the rise of antimicrobial resistance.
“This research is significant, because it shows that the toxin targets essential RNA molecules of other bacteria, effectively rendering them non-functional,” says senior author John Whitney, associate professor for the Department of Biochemistry and Biomedical Sciences at McMaster University in Canada.
“Like humans, bacteria require properly functioning RNA in order to live.”
The team identified the toxin by exploring the antibacterial effector repertoire of the type VI secretion system (T6SS)in P. aeruginosa.
The new toxin is named RhsP2, an enzyme that adds adenosine diphosphate ribose (ADPR) molecules to RNA.
Ribonucleic acid or RNA is found in all living cells. It is structurally similar to DNA, but performs a different function and instead acts as a messenger to carry instructions from DNA to control the synthesis of proteins; this process is called translation.
Modifying RNA by adding ADPR inhibits protein translation.
The types of RNA the toxin can target are remarkably diverse and can inhibit multiple essential cellular processes to induce cell death.
“It’s a total assault on the cell because of how many essential pathways depend on functional RNAs,” explains first author Nathan Bullen, a graduate student in the Department of Biochemistry and Biomedical Sciences.
“This toxin enters its target, hijacks an essential molecule needed for life, and then uses that molecule to disrupt normal processes.”
Whitney says that this newly discovered vulnerability can be exploited for future antibiotic development.