E-Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2021

Redesigning an Anticoccidial Drug for Treatment of Multidrug-Resistant Bacterial Infections (#326)

Hang T. Nguyen 1 , Rietie Venter 2 , Tania Veltman 1 , Ruth Williams 3 , Lisa A. O'Donovan 4 , Cecilia C. Russell 5 , Adam McCluskey 5 , Stephen W. Page 6 , Abiodun D. Ogunniyi 1 , Darren J. Trott 1
  1. Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia
  2. Health and Biomedical Innovation, Clinical and Health Sciences, The University of South Australia, Adelaide, SA, Australia
  3. Adelaide Microscopy, The University of Adelaide, Adelaide, SA, Australia
  4. ARC Centre of Excellence in Plant Energy Biology, School of Agriculture, Food & Wine, The University of Adelaide, Adelaide, SA, Australia
  5. Chemistry, School of Environmental & Life Sciences, The University of Newcastle, Callaghan, NSW, Australia
  6. Neoculi Pty Ltd., Burwood, VIC, Australia

There are renewed global calls for the development of new antimicrobial drugs with novel mechanisms of action, which also prevent further resistance to existing classes against multi-drug resistant pathogens. In this study, the potential of a novel chemical analogue of the anticoccidial robenidine (NCL195) as a drug against multi-drug resistant Gram-positive and Gram-negative bacterial infections was investigated. We showed the minimum inhibitory concentration (MIC) range of NCL195 against methicillin-resistant Staphylococcus aureus isolates was 1-2 μg/mL1. NCL195 demonstrated synergistic activity in combination with subinhibitory concentration of colistin against clinical multidrug-resistant Gram-negative bacterial pathogens, with MICs for NCL195 ranging from 0.5-4 μg/mL for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of subinhibitory concentrations of colistin, whereas NCL195 alone had no activity2. Transmission electron microscopy of S. aureus cells after treatment with NCL1951, or of E. coli and P. aeruginosa after treatment with NCL195+colistin combination confirmed marked ultrastructural changes in membrane morphology, most frequently in the cell envelope2,3. In bioluminescent mouse sepsis challenge models, administration of four oral doses of 50 mg/kg NCL195 (4 hours apart) resulted in significantly reduced S. aureus loads and longer survival times than vehicle-only treated mice. Furthermore, administration of four oral doses of 50 mg/kg NCL195 (4 hours apart) combined with four intraperitoneal doses (4 hours apart) of colistin (0.125 mg/kg) resulted in significant reduction in E. coli loads compared to treatment with NCL195 alone. In addition, treatment with the NCL195+colistin combination resulted in better E. coli clearance than treatment with colistin alone at the same concentrations. We conclude that NCL195 is a potential alternative for further development for specific treatment of Gram-positive bacterial infection or treatment of Gram-negative infection in combination with subinhibitory concentrations of colistin.

  1. Pi, H.; Nguyen, H. T.; Venter, H.; Boileau, A. R.; Woolford, L.; Garg, S.; Page, S. W.; Russell, C. C.; Baker, J. R.; McCluskey, A.; O'Donovan, L. A.; Trott, D. J.; Ogunniyi, A. D. In vitro Activity of Robenidine Analog NCL195 in Combination With Outer Membrane Permeabilizers Against Gram-Negative Bacterial Pathogens and Impact on Systemic Gram-Positive Bacterial Infection in Mice. Frontiers in microbiology 2020, 11, 1556. doi: 10.3389/fmicb.2020.01556.
  2. Nguyen, H. T.; Venter, H.; Veltman, T.; Williams, R.; Anne O'Donovan, L.; Russell, C. C.; McCluskey, A.; Page, S. W.; Ogunniyi, A. D.; Trott, D. J. In vitro synergistic activity of NCL195 in combination with colistin against Gram-negative bacterial pathogens. International journal of antimicrobial agents 2021. doi: 10.1016/j.ijantimicag.2021, 106323.
  3. Nguyen, H. T.; O'Donovan, L. A.; Venter, H.; Russell, C. C.; McCluskey, A.; Page, S. W.; Trott, D. J.; Ogunniyi, A. D. Comparison of Two Transmission Electron Microscopy Methods to Visualize Drug-Induced Alterations of Gram-Negative Bacterial Morphology. Antibiotics (Basel, Switzerland) 2021, 10. doi: 10.3390/antibiotics10030307.