Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2023

IG-01-704: A novel ionophore antibiotic against Gram-positive multidrug-resistant bacterial infections (#151)

Gen (Tom) Li 1 2 , David M. P. De Oliveira 1 2 , Ibrahim M El-Deeb 3 , Mark A. T. Blaskovich 2 4 , Mark von Itzstein 3 , Mark J Walker 1 2
  1. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
  2. Centre for Superbug Solutions, Institute for Molecular Bioscience, Brisbane, QLD, Australia
  3. Institute for Glycocomics, Griffith University, Southport, QLD, Australia
  4. Community for Open Antimicrobial Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

Introduction

 

The Gram-positive bacteria Enterococcus faecium and Staphylococcus aureus have acquired broad-spectrum resistance to several major classes of antibiotics, with new treatments urgently needed[1]. One promising source of new antimicrobials are the ion transporter compounds, termed ionophores which have demonstrated broad-spectrum antimicrobial activity[2]. Here, we sought to identify novel ionophore antimicrobials against multidrug-resistant (MDR) E. faecium and S. aureus and investigate the antimicrobial efficacy of leading candidate(s). 

 

Methods

 

Minimum inhibitory concentration (MIC) assays were undertaken to screen ionophores for antimicrobial activity. Lead compound(s) were further studied for their biological characteristics such as toxicity to human cells, resistance development, time-kill kinetics, antibiotic potentiation, effects on bacterial ion homeostasis and in vivo antimicrobial efficacy. Techniques employed to assess these outcomes were lactate dehydrogenase release assays, development of resistance assays, time-kill experiments, Sensititre microplate MICs, inductively coupled plasma mass spectrometry and murine in vivo wound infection models respectively.

 

Results

 

The ionophore “IG-01-704” demonstrated low MIC values (0.5 – 4 µg/ml) across all tested strains of MDR E. faecium and S. aureus. It was non-toxic to human pharyngeal cells in vitro, and no bacterial resistance developed following 30 consecutive days of serial passage of bacterial growth. In addition, IG-01-704 was bactericidal over 24 hours and potentiated the activity of selected antibiotics. Finally, IG-01-704 effectively perturbed cellular metal ion homeostasis in bacteria and reduced the burden of MDR S. aureus in a murine wound infection model. 

 

Conclusion

 

These results suggest that IG-01-704 is a promising candidate for further investigation to treat Gram-positive MDR pathogens.

 

 

References

 

  1. Li G, Walker MJ, De Oliveira DMP. Vancomycin Resistance in Enterococcus and Staphylococcus aureus. Microorganisms. 2023;11(1):24.
  2. Li G, De Oliveira DMP, Walker MJ. The antimicrobial and immunomodulatory effects of Ionophores for the treatment of human infection. J Inorg Biochem. 2022;227:111661.