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

• Published in: Frontiers in pharmacology Vol. 15; p. 1366459
• Main Authors: Abdulaal, Wesam H, Alhakamy, Nabil A, Asseri, Amer H, Radwan, Mohamed F, Ibrahim, Tarek S, Okbazghi, Solomon Z, Abbas, Hisham A, Mansour, Basem, Shoun, Aly A, Hegazy, Wael A H, Abdel-Halim, Mahmoud Saad
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.03.2024
• Subjects: carbapenems; healthcare; Klebsiella pneumoniae; metallo-β-lactamase inhibitor; pantoprazole; Pharmacology; pantoprazole; carbapenems; metallo-β-lactamase inhibitor; Klebsiella pneumoniae; healthcare
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2024.1366459

The development of resistance to carbapenems in 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 . 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 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 and . 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 .