Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i>
Among the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of β-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy—in which a β-lactamase inhibitor is administered toget...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Microorganisms |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-2607/11/11/2653 |
| _version_ | 1827639204686856192 |
|---|---|
| author | Bogdan M. Benin Trae Hillyer Aylin S. Crugnale Andrew Fulk Caitlyn A. Thomas Michael W. Crowder Matthew A. Smith Woo Shik Shin |
| author_facet | Bogdan M. Benin Trae Hillyer Aylin S. Crugnale Andrew Fulk Caitlyn A. Thomas Michael W. Crowder Matthew A. Smith Woo Shik Shin |
| author_sort | Bogdan M. Benin |
| collection | DOAJ |
| description | Among the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of β-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy—in which a β-lactamase inhibitor is administered together with a β-lactam antibiotic—has proven effective against serine-β-lactamases, there are no currently approved metallo-β-lactamase inhibitors. Herein, we demonstrate that quercetin and its analogs are promising starting points for the further development of safe and effective metallo-β-lactamase inhibitors. Through a combined computational and in vitro approach, taxifolin was found to inhibit VIM-2 expressing <i>P. aeruginosa</i> cell proliferation at <4 μg/mL as part of a triple combination with amoxicillin and clavulanate. Furthermore, we tested this combination in mice with abrasive skin infections. Together, these results demonstrate that flavonol compounds, such as taxifolin, may be developed into effective metallo-β-lactamase inhibitors. |
| first_indexed | 2024-03-09T16:36:18Z |
| format | Article |
| id | doaj.art-7d888425b408427f9c214a1c522020eb |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-09T16:36:18Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-7d888425b408427f9c214a1c522020eb2023-11-24T14:56:48ZengMDPI AGMicroorganisms2076-26072023-10-011111265310.3390/microorganisms11112653Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i>Bogdan M. Benin0Trae Hillyer1Aylin S. Crugnale2Andrew Fulk3Caitlyn A. Thomas4Michael W. Crowder5Matthew A. Smith6Woo Shik Shin7Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USADepartment of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USADepartment of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USADepartment of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USADepartment of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USADepartment of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USADepartment of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USADepartment of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USAAmong the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of β-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy—in which a β-lactamase inhibitor is administered together with a β-lactam antibiotic—has proven effective against serine-β-lactamases, there are no currently approved metallo-β-lactamase inhibitors. Herein, we demonstrate that quercetin and its analogs are promising starting points for the further development of safe and effective metallo-β-lactamase inhibitors. Through a combined computational and in vitro approach, taxifolin was found to inhibit VIM-2 expressing <i>P. aeruginosa</i> cell proliferation at <4 μg/mL as part of a triple combination with amoxicillin and clavulanate. Furthermore, we tested this combination in mice with abrasive skin infections. Together, these results demonstrate that flavonol compounds, such as taxifolin, may be developed into effective metallo-β-lactamase inhibitors.https://www.mdpi.com/2076-2607/11/11/2653metallo-β-lactamasescomputer-aided drug designnatural productsflavonoltaxifolinquercetin |
| spellingShingle | Bogdan M. Benin Trae Hillyer Aylin S. Crugnale Andrew Fulk Caitlyn A. Thomas Michael W. Crowder Matthew A. Smith Woo Shik Shin Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> Microorganisms metallo-β-lactamases computer-aided drug design natural products flavonol taxifolin quercetin |
| title | Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> |
| title_full | Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> |
| title_fullStr | Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> |
| title_full_unstemmed | Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> |
| title_short | Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing <i>Pseudomonas aeruginosa</i> |
| title_sort | taxifolin as a metallo β lactamase inhibitor in combination with augmentin against verona imipenemase 2 expressing i pseudomonas aeruginosa i |
| topic | metallo-β-lactamases computer-aided drug design natural products flavonol taxifolin quercetin |
| url | https://www.mdpi.com/2076-2607/11/11/2653 |
| work_keys_str_mv | AT bogdanmbenin taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT traehillyer taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT aylinscrugnale taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT andrewfulk taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT caitlynathomas taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT michaelwcrowder taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT matthewasmith taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai AT wooshikshin taxifolinasametalloblactamaseinhibitorincombinationwithaugmentinagainstveronaimipenemase2expressingipseudomonasaeruginosai |