Poster Presentation Royal Australian Chemical Institute National Congress 2026

Development of cyclic di-GMP mimics as Gram-negative biofilm disruptors (#617)

Nicholas Fantham 1 , Hana Trenaman 1 , Martina Sanderson-Smith 1 , Danielle Skropeta 1
  1. School of Science, University of Wollongong, Wollongong, NSW, Australia

Human misuse of antibiotics over the last century has rendered many microbes unresponsive to conventional antimicrobial therapies. Opportunistic Gram-negative pathogens, such as multidrug resistant Pseudomonas aeruginosa, pose a significant challenge to global healthcare systems due to their rapid establishment of protective biofilms.1 Biofilm formation is largely regulated by the ubiquitous bacterial second messenger cyclic dimeric guanosine monophosphate (cyclic di-GMP), which is synthesised by diguanylate cyclase (DGC) enzymes through the condensation of two guanosine triphosphate molecules. Interestingly, cyclic di-GMP is known to allosterically inhibit DGCs via an endogenous negative-feedback mechanism. Therefore, synthetic derivatives of cyclic di-GMP are considered potential biofilm disruptors and are classified as Next Generation Antimicrobials (NGAs).2-4

This project explores the rational design and synthesis of novel cyclic di-GMP mimics targeting WspR, a key DGC from P. aeruginosa. We report the development of isatin and purine-based cyclic di-GMP analogues. Molecular docking of over 500 novel structures using AutoDock-GPU revealed key binding interactions, shaping our final synthetic targets. Biological evaluation will also be presented, with these studies aiming to inform future antibiofilm therapeutic development and highlight the ongoing clinical challenges posed by bacterial biofilms.

 

 

  1. Thi, M. T. T.; Wibowo, D.; Rehm, B. H. A. Pseudomonas aeruginosa Biofilms. International Journal of Molecular Sciences 2020, 21 (22). DOI: 10.3390/ijms21228671.
  2. Gadar, K.; McCarthy, R. R. Using Next Generation Antimicrobials to Target the Mechanisms of Infection. NPJ Antimicrobials and Resistance 2023, 1 (1), 11. DOI: 10.1038/s44259-023-00011-6.
  3. Fernicola, S.; Torquati, I.; Paiardini, A.; Giardina, G.; Rampioni, G.; Messina, M.; Leoni, L.; Del Bello, F.; Petrelli, R.; Rinaldo, S.; et al. Synthesis of Triazole-Linked Analogues of C-di-GMP and Their Interactions with Diguanylate Cyclase. Journal of Medicinal Chemistry 2015, 58 (20), 8269-8284. DOI: 10.1021/acs.jmedchem.5b01184.
  4. Zhou, J.; Watt, S.; Wang, J.; Nakayama, S.; Sayre, D. A.; Lam, Y. F.; Lee, V. T.; Sintim, H. O. Potent Suppression of C-di-GMP Synthesis via I-site Allosteric Inhibition of Diguanylate Cyclases with 2'-F-C-di-GMP. Bioorganic & Medicinal Chemistry 2013, 21 (14), 4396-4404. DOI: 10.1016/j.bmc.2013.04.050.