دورية أكاديمية
3- O -Substituted Quercetin: an Antibiotic-Potentiating Agent against Multidrug-Resistant Gram-Negative Enterobacteriaceae through Simultaneous Inhibition of Efflux Pump and Broad-Spectrum Carbapenemases.
| العنوان: | 3- O -Substituted Quercetin: an Antibiotic-Potentiating Agent against Multidrug-Resistant Gram-Negative Enterobacteriaceae through Simultaneous Inhibition of Efflux Pump and Broad-Spectrum Carbapenemases. |
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| المؤلفون: | Lee T; Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea., Lee S; Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea., Kim MK; Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea., Ahn JH; Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea., Park JS; Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Yuseong-gu, Daejeon 34141, Korea., Seo HW; Infectious Disease Research Center, Korea Research Institute of Bioscience & Biotechnology, Yuseong-gu, Daejeon 34141, Korea., Park KH; Department of Infectious Disease, Kyung Hee University School of Medicine, Seoul 02447, Korea., Chong Y; Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 05029, Korea. |
| المصدر: | ACS infectious diseases [ACS Infect Dis] 2024 May 10; Vol. 10 (5), pp. 1624-1643. Date of Electronic Publication: 2024 Apr 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : ACS Publications, [2015]- |
| مواضيع طبية MeSH: | beta-Lactamases*/metabolism , Anti-Bacterial Agents*/pharmacology , Anti-Bacterial Agents*/chemistry , Drug Resistance, Multiple, Bacterial*/drug effects , Bacterial Proteins*/antagonists & inhibitors , Bacterial Proteins*/metabolism , Molecular Docking Simulation* , Microbial Sensitivity Tests* , Quercetin*/pharmacology , Quercetin*/chemistry, Animals ; Mice ; beta-Lactamase Inhibitors/pharmacology ; beta-Lactamase Inhibitors/chemistry ; Enterobacteriaceae/drug effects ; Enterobacteriaceae/enzymology ; Carbapenem-Resistant Enterobacteriaceae/drug effects ; Drug Synergism ; Enterobacteriaceae Infections/drug therapy ; Enterobacteriaceae Infections/microbiology ; Female |
| مستخلص: | The discovery of safe and efficient inhibitors against efflux pumps as well as metallo-β-lactamases (MBL) is one of the main challenges in the development of multidrug-resistant (MDR) reversal agents which can be utilized in the treatment of carbapenem-resistant Gram-negative bacteria. In this study, we have identified that introduction of an ethylene-linked sterically demanding group at the 3-OH position of the previously reported MDR reversal agent di-F-Q endows the resulting compounds with hereto unknown multitarget inhibitory activity against both efflux pumps and broad-spectrum β-lactamases including difficult-to-inhibit MBLs. A molecular docking study of the multitarget inhibitors against efflux pump, as well as various classes of β-lactamases, revealed that the 3- O -alkyl substituents occupy the novel binding sites in efflux pumps as well as carbapenemases. Not surprisingly, the multitarget inhibitors rescued the antibiotic activity of a carbapenem antibiotic, meropenem (MEM), in NDM-1 (New Delhi Metallo-β-lactamase-1)-producing carbapenem-resistant Enterobacteriaceae (CRE), and they reduced MICs of MEM more than four-fold (synergistic effect) in 8-9 out of 14 clinical strains. The antibiotic-potentiating activity of the multitarget inhibitors was also demonstrated in CRE-infected mouse model. Taken together, these results suggest that combining inhibitory activity against two critical targets in MDR Gram-negative bacteria, efflux pumps, and β-lactamases, in one molecule is possible, and the multitarget inhibitors may provide new avenues for the discovery of safe and efficient MDR reversal agents. |
| فهرسة مساهمة: | Keywords: MDR reversal agent; carbapenemases; efflux pump, carbapenem-resistant Enterobacteriaceae; multitarget inhibitor |
| المشرفين على المادة: | EC 3.5.2.6 (beta-Lactamases) 0 (Anti-Bacterial Agents) 0 (Bacterial Proteins) 9IKM0I5T1E (Quercetin) EC 3.5.2.6 (carbapenemase) 0 (beta-Lactamase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240423 Date Completed: 20240510 Latest Revision: 20240613 |
| رمز التحديث: | 20240614 |
| DOI: | 10.1021/acsinfecdis.3c00715 |
| PMID: | 38652574 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 2373-8227 |
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| DOI: | 10.1021/acsinfecdis.3c00715 |