Venom is a remarkable example of convergent evolution having appeared independently across many bacteria, plant, fungi, and animal lineages. This ability to interact with host physiological pathways aid venomous organisms both in defence and predation. Interaction with venomous organisms affect millions of people annually resulting in significant morbidity, mortality, and associated economic burden.
We reason that as venoms need to hijack the physiological pathways of host cells, diverse venoms may utilise overlapping strategies to gain cell entry or cause damage. Using a whole-genome CRISPR screening approach we found that venom from the Australian bluebottle jellyfish (Physalia utriculus) requires GPI-anchor and proteoglycan biosynthesis pathways to cause cell death. Remarkably we previously found the prteoglycan pathway to be required by the Atlantic Sea Nettle jellyfish (Chrysaora quinquecirrha) and Spitting Cobras (Naja pallida and Naja nigricollis). We confirmed these findings genetically and pharmacologically and used the results to predict new drugs that could act as venom antidotes. One such drug was observed to have broad anti-venom activity observed through behavioural assays and could have translational promise for preventing the pain associated with bluebottle envenoming. We argue that using CRISPR screening to classify venom mechanisms of actions functionally can provide fundamental new insight and help us develop broad spectrum antidotes for medically relevant and painful venoms.