Oral + Poster 9th Venoms to Drugs 2026

From ant venom to antibiofilm drug leads for treating gut disorders (#004)

Bernhard Jandl 1 2 3 , Sofiia Bolkhovetska 1 , Martina A. Höllwarth 1 , Roel Kerkers 4 , Doris Moser 5 , Michaela Lang 6 7 , Athanasios Makristathis 8 , Christoph Gasche 7 9 , Markus Muttenthaler 1 3
  1. Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, Vienna, Austria
  2. Research School of Chemistry, ANU College of Science and Medicine, The Australian National University, Canberra, Australian Capital Territory, Australia
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  4. School of Life Sciences and Environmental Technology, Avans University of Applied Science, Breda, The Netherlands
  5. Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria
  6. Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, Vienna, Austria
  7. Department of Internal Medicine 3, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
  8. Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
  9. Loha for Life, Center for Gastroenterology and Iron Deficiency, Vienna, Austria

Gastrointestinal biofilms are mucus-adherent prokaryotic communities embedded in a protective matrix of extracellular polymeric substances, including DNA, proteins, polysaccharides and lipids. These biofilms are associated with chronic gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD; Crohn’s disease, ulcerative colitis)1-3 – together affecting >10% of the global population and imposing a substantial socioeconomic burden. Our recent high-powered (>1,100 participants) clinical study found that gastrointestinal biofilms occur in ~60% of patients with IBS and ~30% with IBD, compared with only 6% of healthy individuals.4 Despite their high prevalence, no biofilm-specific therapeutics currently exist, underscoring an urgent unmet medical need for developing such therapies.

Animal venom is a rich source of bioactive peptides that have been fine-tuned throughout evolution for diverse physiological activities. Numerous venom-derived antimicrobial peptides (AMPs) have potent antimicrobial activity, representing valuable therapeutic opportunities for treating infectious diseases. Such AMPs are a particularly promising source for developing anti-gut-biofilm compounds, owing to their broad-spectrum antimicrobial activity, high selection pressures, and ability to circumvent antibiotic resistance mechanisms. Here, we present the first structure-stability-activity relationship (SSAR) investigation of the ant venom peptide Ponericin W5 – a very potent AMP with low-nanomolar antimicrobial activity (MIC=20 nM) against methicillin-resistant Staphylococcus aureus (MRSA), representing a 100-fold higher potency than vancomycin (MICMRSA=2 µM). Specifically, we employed an SSAR-guided drug discovery approach that integrated medicinal chemistry strategies—including head-to-tail cyclisation, truncation, lipidation, global Ile-to-Val substitution, and peptide mirror designs—with comprehensive anti-gut-biofilm profiling to evaluate antimicrobial, antifungal, and antibiofilm activities as well as cytotoxicity, haemotoxicity, therapeutic window, and intestinal stability. This approach produced potent, gut-stable antibiofilm peptides, with D-PonW5[I6V;I13V] as the most promising lead. D-PonW5[I6V;I13V] exhibited low micromolar biofilm eradication activity (MBEC=1.6–3.2 µM) against Gram-positive clinical isolates from intestinal biofilms of IBS patients, supporting it as a new drug lead for biofilm-associated gut disorders. Our findings also highlighted that our all-D mirror AMPs, combined with a global Ile-to-Val substitution, constitute an efficient, cost-saving (up to 95%) strategy for developing potent, highly stable antibiofilm peptide drug leads. This study lays the groundwork for future nature-derived antibiofilm drug development efforts, with promise for the development of oral first-in-class therapeutics to treat intestinal bacterial biofilms in patients with chronic gut disorders.

  1. Gastrointestinal Biofilms: Endoscopic Detection, Disease Relevance, and Therapeutic Strategies. Jandl B, Dighe S, Baumgartner M, Makristathis A, Gasche C and Muttenthaler M. Gastroenterology 2024, 167 (6), 1098-1112.e1095.
  2. Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities. Jandl B, Dighe S, Gasche C, Makristathis A and Muttenthaler M. Clinical Microbiology Reviews 2024, 37 (3), e00133-00123.
  3. Gastrointestinal biofilms in health and disease. Motta J-P, Wallace JL, Buret AG, Deraison C and Vergnolle N. Nature Reviews Gastroenterology & Hepatology 2021, 18 (5), 314-334.
  4. Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis. Baumgartner M, Lang M, Holley H, Crepaz D, Hausmann B, Pjevac P, Moser D, Haller F, Hof F, Beer A, Orgler E, Frick A, Khare V, Evstatiev R, Strohmaier S, Primas C, Dolak W, Köcher T, Klavins K, Rath T, Neurath MF, Berry D, Makristathis A, Muttenthaler M and Gasche C. Gastroenterology 2021, 161 (4), 1245-1256.e1220.