Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections
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 <i>Staphylococcus aureus</i> isolates either susceptible or resistant to methicil...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/6/727 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hang Thi Nguyen |
| collection | DOAJ |
| description | 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 <i>Staphylococcus aureus</i> isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen <i>Staphylococcus pseudintermedius</i>, 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 <i>Acinetobacter baumannii</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumoniae,</i> and <i>Pseudomonas aeruginosa</i> (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 <i>S. aureus</i> 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. |
| first_indexed | 2024-03-10T10:21:42Z |
| format | Article |
| id | doaj.art-a686e5cc14e94027b21eee985f1918fd |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T10:21:42Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-a686e5cc14e94027b21eee985f1918fd2023-11-22T00:24:03ZengMDPI AGAntibiotics2079-63822021-06-0110672710.3390/antibiotics10060727Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial InfectionsHang Thi Nguyen0Mahmud T. Morshed1Daniel Vuong2Andrew Crombie3Ernest Lacey4Sanjay Garg5Hongfei Pi6Lucy Woolford7Henrietta Venter8Stephen W. Page9Andrew M. Piggott10Darren J. Trott11Abiodun D. Ogunniyi12Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, AustraliaDepartment of Molecular Sciences, Macquarie University, Sydney, NSW 2109, AustraliaMicrobial Screening Technologies Pty. Ltd., Smithfield, NSW 2164, AustraliaMicrobial Screening Technologies Pty. Ltd., Smithfield, NSW 2164, AustraliaDepartment of Molecular Sciences, Macquarie University, Sydney, NSW 2109, AustraliaClinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaAustralian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, AustraliaSchool of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, AustraliaHealth and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, AustraliaAdvanced Veterinary Therapeutics, Newtown, NSW 2042, AustraliaDepartment of Molecular Sciences, Macquarie University, Sydney, NSW 2109, AustraliaAustralian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, AustraliaAustralian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, SA 5371, AustraliaOur 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 <i>Staphylococcus aureus</i> isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen <i>Staphylococcus pseudintermedius</i>, 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 <i>Acinetobacter baumannii</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumoniae,</i> and <i>Pseudomonas aeruginosa</i> (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 <i>S. aureus</i> 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.https://www.mdpi.com/2079-6382/10/6/727<i>Staphylococcus pseudintermedius</i><i>Staphylococcus aureus</i>benzguinolsnidulinsGram-negativeantimicrobial resistance |
| spellingShingle | 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 Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections Antibiotics <i>Staphylococcus pseudintermedius</i> <i>Staphylococcus aureus</i> benzguinols nidulins Gram-negative antimicrobial resistance |
| title | Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections |
| title_full | Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections |
| title_fullStr | Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections |
| title_full_unstemmed | Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections |
| title_short | Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections |
| title_sort | evaluation of benzguinols as next generation antibiotics for the treatment of multidrug resistant bacterial infections |
| topic | <i>Staphylococcus pseudintermedius</i> <i>Staphylococcus aureus</i> benzguinols nidulins Gram-negative antimicrobial resistance |
| url | https://www.mdpi.com/2079-6382/10/6/727 |
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