Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections
Hang Thi Nguyen,
Mahmud T. Morshed,
Daniel Vuong,
Andrew Crombie,
Ernest Lacey,
Sanjay Garg,
Hongfei Pi,
Lucy Woolford,
Henrietta Venter,
Stephen W. Page,
Andrew M. Piggott,
Darren J. Trott,
Abiodun D. Ogunniyi
Affiliations
Hang Thi Nguyen
Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia
Mahmud T. Morshed
Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
Daniel Vuong
Microbial Screening Technologies Pty. Ltd., Smithfield, NSW 2164, Australia
Andrew Crombie
Microbial Screening Technologies Pty. Ltd., Smithfield, NSW 2164, Australia
Ernest Lacey
Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
Sanjay Garg
Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Hongfei Pi
Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia
Lucy Woolford
School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia
Henrietta Venter
Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Stephen W. Page
Advanced Veterinary Therapeutics, Newtown, NSW 2042, Australia
Andrew M. Piggott
Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
Darren J. Trott
Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia
Abiodun D. Ogunniyi
Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia
Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes.
