Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

Antibiotics

Stephen W. Page¹  Abiodun D. Ogunniyi²  Hongfei Pi²  Darren J. Trott²  Hang Thi Nguyen²  Sanjay Garg³  Mahmud T. Morshed⁴  Andrew M. Piggott⁴  Ernest Lacey⁴  Henrietta Venter⁵  Daniel Vuong⁶  Andrew Crombie⁶  Lucy Woolford⁷ 

[1] Advanced Veterinary Therapeutics, Newtown, NSW 2042, Australia;Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia;Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia;Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia;Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia;Microbial Screening Technologies Pty. Ltd., Smithfield, NSW 2164, Australia;School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, Australia;

关键词: Staphylococcus pseudintermedius;    Staphylococcus aureus;    benzguinols;    nidulins;    Gram-negative;    antimicrobial resistance;   

DOI  :  10.3390/antibiotics10060727

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown