Gastrointestinal disorders are a group of chronic health conditions that include inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), and colorectal cancers that affect millions globally. A hallmark is microbial dysbiosis, which promotes the expansion of non-commensal bacteria capable of forming biofilms.1,2 The increased abundance of these gut biofilms in patients with IBS and IBD underscores their important role in disease pathogenesis.3 Conventional antibiotics used in clinical practice are often ineffective against such biofilms due to their low gut availability, limited penetration into the biofilm matrix, and presence of antimicrobial-resistant bacteria, highlighting the need for novel therapeutics capable of reaching and eradicating these biofilms.
Across the tree of life, animals have been exposed to microbial pressures and have evolved antimicrobial peptides (AMPs) as innate defence mechanisms. While amphibians and marsupials produce AMP-rich skin and pouch secretions to limit microbial colonisation, AMPs are also found in venoms to safeguard prey stores, nests, and colonies from microbial threats. Harnessing this biodiversity, we synthesised peptides from snake, bee, and ant venoms and tested them against biofilm-forming bacterial isolates from patients with IBS. We demonstrated potent antibiofilm activity and investigated the structural features governing these effects. We then optimised biofilm specificity and gastrointestinal stability, and engineered more drug-like molecules suitable for oral delivery and treatment of intestinal biofilms. Our findings highlight an intriguing new therapeutic application of venoms as a source of antimicrobials that we exploited to develop new drug leads for treating biofilms associated with chronic gastrointestinal disorders.