Viper-active: Snake Venom Microbiome as a Source for Bacterially-derived Molecule Discovery

Proposal Summary Historically, venoms have acted as a ‘double-edged sword’ in their impacts on human health. Snake venoms are complex cocktails of bioactive toxins that have been a prolific source of pharmacologically useful molecules for antibacterial, anticancer, pain management, and cardiac/hematological drug discovery and development. For

example, cathelicidin from the Colubrinae snake species Sinonatrix annularis, serves as a critical effector in host immune response against microbial infections. At the same time, snakebite envenomation has been recently reinstated to the list of category A Neglected Tropical Diseases by the World Health Organization (WHO), with a

3-5% risk of mortality and documented long-term, multi-organ effects after initial injury. Furthermore, three- quarters of snake bite victims develop secondary mono or poly-microbial envenomation wound infections, although the source of infection is still unknown. Recent studies have revealed a diverse venom microbiome,

which is distinct from the oral microbiota. Venom microbes are thought to be opportunistic colonizers, as the snake fang and venom gland are structurally comparable to a clinical catheterization assembly which is open to the environment and the snake oral cavity. Advances in DNA sequencing and genome mining have revealed

stress-adapted metabolism pathways in venom-associated bacterial isolates that may allow for their persistence in the venom microenvironment. However, there has been no investigation of the full bacterial community composition or specialized bacterial metabolites which may play a role in the venom toxin cocktail. In our

research, we aim to characterize the genomic and taxonomic diversity of bacteria in the venom gland and understand the chemical diversity and activity of molecules produced by venom-associated bacteria. Throughout this study, we will bridge field, laboratory, and computational studies using multi-omic and bioassay techniques

to understand the biosynthetic potential of bacteria identified in venom. Moreover, we will identify bioactive molecules in venom-derived bacteria that have been underexplored. Overall, we hypothesize that venom- associated bacteria hold the potential to produce bioactive compounds that pose an underexplored risk to human

health and immense chemical potential. We anticipate these efforts will add to the growing body of evidence exploring the venom microbiome and assist with future public health guidelines for snakebite treatment.