7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump
<b>Background/Objectives:</b> Previously, we reported that 3-<i>O</i>-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing <i>P. aeruginosa</i> through simultaneous inhibition of MB...
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2024-12-01
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| author | Seongyeon Lee Taegum Lee Mi Kyoung Kim Joong Hoon Ahn Seri Jeong Ki-Ho Park Youhoon Chong |
| author_facet | Seongyeon Lee Taegum Lee Mi Kyoung Kim Joong Hoon Ahn Seri Jeong Ki-Ho Park Youhoon Chong |
| author_sort | Seongyeon Lee |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Previously, we reported that 3-<i>O</i>-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing <i>P. aeruginosa</i> through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3-<i>O</i>-alkyl di-F-Q was observed only at high and potentially toxic concentrations (32 mg/L). <b>Methods:</b> As both MBLs and efflux pumps reside in the periplasm of Gram-negative bacteria, their inhibitors should accumulate in the periplasmic space. However, the outer membrane porins, the major entry pathway in Gram-negative bacteria, allow the passive diffusion of hydrophilic polar molecules across the outer membrane. Thus, we reasoned that the introduction of a polar substituent at 7-OH position of 3-<i>O</i>-alkyl di-F-Q would enhance its periplasmic concentration to result in potentiation of ATM at lower concentrations. <b>Results:</b> The title compound <b>5</b> exhibited inhibitory activity against NDM-1 as well as the efflux pump of <i>P. aeruginosa</i>, which resulted in synergistical potentiation of ATM. A combination of ATM (8 mg/L) and <b>5</b> (8 mg/L) inhibited 80% of the ATM-resistant CPPA, while ATM alone did not show any inhibition. In addition, only 4 mg/L of <b>5</b> was needed to reduce the MIC<sub>90</sub> of ATM four-fold in ATM-resistant CPPA (n = 15). The time–kill data further supported the effectiveness of the combined treatment of ATM with <b>5</b>, and the combination of ATM (1xMIC) with 8 mg/L of <b>5</b> showed bactericidal effects in every bacterial strain tested (PA-002, <i>bla</i><sub>IMP</sub>, PA-003, <i>bla</i><sub>VIM</sub>, PA-014, <i>bla</i><sub>GES</sub>, and PA-017, <i>bla</i><sub>NDM</sub>) by reducing the bacterial loads by 5.1 log<sub>10</sub>~8.9 log<sub>10</sub>. <b>Conclusions:</b> The title compound <b>5</b> exhibited inhibitory activity against NDM-1 as well as the efflux pump of <i>P. aeruginosa</i>, and the combined inhibitory activity resulted in synergistical potentiation of ATM. It should be noted that most CPPA isolates tested were sensitized to 8 mg/L of ATM upon combination with 4~8 mg/L of <b>5</b>. |
| format | Article |
| id | doaj-art-e495719ca49346848ca92af117710521 |
| institution | DOAJ |
| issn | 2079-6382 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-e495719ca49346848ca92af1177105212025-08-20T02:53:41ZengMDPI AGAntibiotics2079-63822024-12-011312120210.3390/antibiotics131212027-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux PumpSeongyeon Lee0Taegum Lee1Mi Kyoung Kim2Joong Hoon Ahn3Seri Jeong4Ki-Ho Park5Youhoon Chong6Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of KoreaDepartment of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of KoreaDepartment of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of KoreaDepartment of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of KoreaDepartment of Laboratory Medicine, Hallym University College of Medicine, Chuncheon 24252, Republic of KoreaDepartment of Infectious Disease, Kyung Hee University School of Medicine, Seoul 02447, Republic of KoreaDepartment of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea<b>Background/Objectives:</b> Previously, we reported that 3-<i>O</i>-alkyl difluoroquercetins (di-F-Q) potentiates the antimicrobial activity of aztreonam (ATM) against metallo-β-lactamase (MBL)-producing <i>P. aeruginosa</i> through simultaneous inhibition of MBLs and efflux pumps. However, the ATM-potentiating activity of the 3-<i>O</i>-alkyl di-F-Q was observed only at high and potentially toxic concentrations (32 mg/L). <b>Methods:</b> As both MBLs and efflux pumps reside in the periplasm of Gram-negative bacteria, their inhibitors should accumulate in the periplasmic space. However, the outer membrane porins, the major entry pathway in Gram-negative bacteria, allow the passive diffusion of hydrophilic polar molecules across the outer membrane. Thus, we reasoned that the introduction of a polar substituent at 7-OH position of 3-<i>O</i>-alkyl di-F-Q would enhance its periplasmic concentration to result in potentiation of ATM at lower concentrations. <b>Results:</b> The title compound <b>5</b> exhibited inhibitory activity against NDM-1 as well as the efflux pump of <i>P. aeruginosa</i>, which resulted in synergistical potentiation of ATM. A combination of ATM (8 mg/L) and <b>5</b> (8 mg/L) inhibited 80% of the ATM-resistant CPPA, while ATM alone did not show any inhibition. In addition, only 4 mg/L of <b>5</b> was needed to reduce the MIC<sub>90</sub> of ATM four-fold in ATM-resistant CPPA (n = 15). The time–kill data further supported the effectiveness of the combined treatment of ATM with <b>5</b>, and the combination of ATM (1xMIC) with 8 mg/L of <b>5</b> showed bactericidal effects in every bacterial strain tested (PA-002, <i>bla</i><sub>IMP</sub>, PA-003, <i>bla</i><sub>VIM</sub>, PA-014, <i>bla</i><sub>GES</sub>, and PA-017, <i>bla</i><sub>NDM</sub>) by reducing the bacterial loads by 5.1 log<sub>10</sub>~8.9 log<sub>10</sub>. <b>Conclusions:</b> The title compound <b>5</b> exhibited inhibitory activity against NDM-1 as well as the efflux pump of <i>P. aeruginosa</i>, and the combined inhibitory activity resulted in synergistical potentiation of ATM. It should be noted that most CPPA isolates tested were sensitized to 8 mg/L of ATM upon combination with 4~8 mg/L of <b>5</b>.https://www.mdpi.com/2079-6382/13/12/1202<i>Pseudomonas aeruginosa</i>metallo-β-lactamaseefflux pumpsimultaneous inhibitionaztreonampotentiation |
| spellingShingle | Seongyeon Lee Taegum Lee Mi Kyoung Kim Joong Hoon Ahn Seri Jeong Ki-Ho Park Youhoon Chong 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump Antibiotics <i>Pseudomonas aeruginosa</i> metallo-β-lactamase efflux pump simultaneous inhibition aztreonam potentiation |
| title | 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump |
| title_full | 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump |
| title_fullStr | 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump |
| title_full_unstemmed | 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump |
| title_short | 7-<i>O</i>-Carboxylic Acid-Substituted 3-<i>O</i>-Alkyl Difluoroquercetin; An Aztreonam-Potentiating Agent Against Carbapenemase-Producing <i>Pseudomonas aeruginosa</i> Through Simultaneous Inhibition of Metallo-β-Lactamase and Efflux Pump |
| title_sort | 7 i o i carboxylic acid substituted 3 i o i alkyl difluoroquercetin an aztreonam potentiating agent against carbapenemase producing i pseudomonas aeruginosa i through simultaneous inhibition of metallo β lactamase and efflux pump |
| topic | <i>Pseudomonas aeruginosa</i> metallo-β-lactamase efflux pump simultaneous inhibition aztreonam potentiation |
| url | https://www.mdpi.com/2079-6382/13/12/1202 |
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