An international research collaboration has discovered a new bacteria-killing toxin that shows promise of impacting superbug infectious diseases. The discovery of this growth-inhibiting toxin, which bacteria inject into rival bacteria to gain a competitive advantage, was published in the journal Nature.

Researchers were studying how bacteria secrete antibacterial molecules when they came across a new toxin. This toxin was an antibacterial enzyme, one the researchers had never seen before. The authors identified this enazyme as a type VI secretion effector, Tas1, in the opportunistic pathogen Pseudomonas aeruginosa.  

After determining the molecular structure of this toxin, Tas1, the authors realized that it resembles enzymes that synthesize a well-known bacterial signalling molecule called (p)ppGpp. This molecule normally helps bacteria survive under stressful conditions, such as exposure to antibiotics.

"The 3D structure of this toxin was at first puzzling because no known toxins look like enzymes that make (p)ppGpp, and (p)ppGpp itself is not a toxin," said the author.

Suspecting the toxin might kill bacteria by overproducing harmful quantities of (p)ppGpp, the  team shared their findings with a collaborator who specializes in (p)ppGpp signaling, examined the activity of the newly discovered enzyme. They soon realized that rather than making (p)ppGpp, this enzyme instead produced a poorly understood but related molecule called (p)ppApp. Somehow, the production of (p)ppApp was harmful to bacteria.

Tas1 pyrophosphorylates adenosine nucleotides to produce (p)ppApp at rates of nearly 180,000 molecules per minute. The researchers determined that the rapid production of (p)ppApp by this enzyme toxin depletes cells of a molecule called ATP, thereby resulting in target cell death. ATP is often referred to as the 'energy currency of the cell' so when the supply of ATP is exhausted, essential cellular processes are compromised and the bacteria die.

"I find it absolutely fascinating that evolution has essentially "repurposed" an enzyme that normally helps bacteria survive antibiotic treatment and, instead, has deployed it for use as an antibacterial weapon," said the co-senior author.

https://www.nature.com/articles/s41586-019-1735-9