Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections
Files
(Published version)
Date
2021
Authors
Nguyen, H.T.
Morshed, M.T.
Vuong, D.
Crombie, A.
Lacey, E.
Garg, S.
Pi, H.
Woolford, L.
Venter, H.
Page, S.W.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Antibiotics, 2021; 10(6):727-1-727-17
Statement of Responsibility
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, and Abiodun D. Ogunniyi
Conference Name
Abstract
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 mg/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 mg/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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).