Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae .

Autor: Abdulaal WH; Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia., Alhakamy NA; Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.; Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia.; Mohamed Saeed Tamer Chair for Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia., Asseri AH; Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.; Centre for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia., Radwan MF; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Ibrahim TS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia., Okbazghi SZ; Global Analytical and Pharmaceutical Development, Alexion Pharmaceuticals, New Haven, CT, United States., Abbas HA; Microbiology and Immunology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt., Mansour B; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt., Shoun AA; Microbiology and Immunology Department, Faculty of Pharmacy, El Salehey El Gadida University, Sharkiya, Egypt., Hegazy WAH; Microbiology and Immunology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.; Pharmacy Program, Department of Pharmaceutical Sciences, Oman College of Health Sciences, Muscat, Oman., Abdel-Halim MS; Microbiology and Immunology Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2024 Mar 12; Vol. 15, pp. 1366459. Date of Electronic Publication: 2024 Mar 12 (Print Publication: 2024).
DOI: 10.3389/fphar.2024.1366459
Abstrakt: The development of resistance to carbapenems in Klebsiella pneumoniae due to the production of metallo-β-lactamases (MBLs) is a critical public health problem because carbapenems are the last-resort drugs used for treating severe infections of extended-spectrum β-lactamases (ESBLs) producing K. pneumoniae . Restoring the activity of carbapenems by the inhibition of metallo-β-lactamases is a valuable approach to combat carbapenem resistance. In this study, two well-characterized clinical multidrug and carbapenem-resistant K. pneumoniae isolates were used. The sub-inhibitory concentrations of pantoprazole and the well-reported metallo-β-lactamase inhibitor captopril inhibited the hydrolytic activities of metallo-β-lactamases, with pantoprazole having more inhibiting activities. Both drugs, when used in combination with meropenem, exhibited synergistic activities. Pantoprazole could also downregulate the expression of the metallo-β-lactamase genes bla NDM and bla VIM . A docking study revealed that pantoprazole could bind to and chelate zinc ions of New Delhi and Verona integron-encoded MBL (VIM) enzymes with higher affinity than the control drug captopril and with comparable affinity to the natural ligand meropenem, indicating the significant inhibitory activity of pantoprazole against metallo-β-lactamases. In conclusion, pantoprazole can be used in combination with meropenem as a new strategy for treating serious infections caused by metallo-β-lactamases producing K. pneumoniae .
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Abdulaal, Alhakamy, Asseri, Radwan, Ibrahim, Okbazghi, Abbas, Mansour, Shoun, Hegazy and Abdel-Halim.)
Databáze: MEDLINE
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