Nguyen, H.T.Morshed, M.T.Vuong, D.Crombie, A.Lacey, E.Garg, S.Pi, H.Woolford, L.Venter, H.Page, S.W.Piggott, A.M.Trott, D.J.Ogunniyi, A.D.2025-07-112025-07-112021Antibiotics, 2021; 10(6):727-1-727-172079-63822079-6382https://hdl.handle.net/2440/145856Our 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.en© 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/).Staphylococcus pseudintermedius; Staphylococcus aureus; benzguinols; nidulins; Gramnegative; antimicrobial resistance; colistin; bioluminescent mouse model; cytotoxicity; minimum inhibitory concentrationJournal article10.3390/antibiotics100607272024-03-28580594Woolford, L. [0000-0001-7271-2937]Trott, D.J. [0000-0002-8297-5770]Ogunniyi, A.D. [0000-0001-9308-5629]