Poster Presentation 11th Annual Conference of the International Chemical Biology Society 2022

Trojan horse antibiotics - exploiting siderophores to overcome antimicrobial resistance (#167)

Beth Rayner 1 2 , Anthony D Verderosa 1 2 , Vito Ferro 2 3 , Mark A.T Blaskovich 1 2 3
  1. Centre for Superbug Solutions, Institute for Molecular Bioscience, Brisbane, QLD, Australia
  2. Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, QLD, Australia
  3. School of Chemistry and Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

Antimicrobial resistance (AMR) is a rapidly developing global pandemic, with current estimates suggesting that by 2050 more than 10 million deaths annually will be attributed to AMR.1 Exacerbating this issue is a severe gap in antibiotic development, with no new clinically relevant classes of antibiotics developed in the last two decades.2 The combination of the rapidly increasing emergence of resistance and scarcity of new antibiotics in the clinical pipeline means there is an urgent need for new efficacious treatment strategies. One promising solution, known as the ‘Trojan horse’ approach, hijacks the iron transport system of bacteria to deliver antibiotics directly into cells – effectively tricking bacteria into killing themselves.3 This transport system uses natively produced siderophores, which are small molecules with a high affinity for iron.3 By linking antibiotics to siderophores, to make siderophore-antibiotic conjugates, the activity of existing antibiotics can potentially be reinvigorated.3 The success of this strategy was recently exemplified with the clinical release of cefiderocol, a cephalosporin-siderophore conjugate with potent antibacterial activity against carbapenem-resistant and multi-drug resistant Gram-negative bacilli.4,5 This document will provide an overview of the ‘Trojan horse’ strategy before detailing how we will be expanding this approach to multiple classes of antibiotics (e.g., lipopeptides, β-lactams, aminoglycosides, nitroimidazoles, fluoroquinolones and oxazolidinones).

  1. Kong, H.; Cheng, W.; Wei, H.; Yuan, Y.; progress in siderophore-antibiotic conjugates. Eur.J. Med. Chem. 2019, 182, 111615.
  2. Khan, A.; Singh, P.; Srivastava, A., Synthesis, nature and utility of universal iron chelator – Siderophore: A review. Microbiol. Res. 2018, 212-213, 103-111.
  3. Miethke, M.; Kraushaar, T.; Marahiel, M. A., Uptake of xenosiderophores in Bacillus subtilis occurs with high affinity and enhances the folding stabilities of substrate binding proteins. FEBS Lett. 2013, 587 (2), 206-213.
  4. Breukink, E.; de Kruijff, B., Lipid II as a target for antibiotics. Nat. Rev. Drug Discovery 2006, 5 (4), 321-323.
  5. Rajagopal, M.; Walker, S., Envelope Structures of Gram-Positive Bacteria. Curr. Top. Microbiol. Immunol. 2017, 404, 1-44.