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. 2024 Mar 12:15:1366459.
doi: 10.3389/fphar.2024.1366459. eCollection 2024.

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

Wesam H Abdulaal  1 , Nabil A Alhakamy  2   3   4 , Amer H Asseri  5   6 , Mohamed F Radwan  7 , Tarek S Ibrahim  7 , Solomon Z Okbazghi  8 , Hisham A Abbas  9 , Basem Mansour  10 , Aly A Shoun  11 , Wael A H Hegazy  9   12 , Mahmoud Saad Abdel-Halim  9
Affiliations

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

Wesam H Abdulaal et al. Front Pharmacol. .

Abstract

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.

Keywords: Klebsiella pneumoniae; carbapenems; healthcare; metallo-β-lactamase inhibitor; pantoprazole.

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Conflict of interest statement

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.

Figures

FIGURE 1
FIGURE 1
Effect of the sub-minimum inhibitory concentration (MIC) of pantoprazole and captopril on the growth of tested isolates. No significant difference was found in the growth of the test isolate by either captopril or pantoprazole; non-significant (ns): p > 0.05.
FIGURE 2
FIGURE 2
Potentiation of meropenem antibacterial activity against the tested isolates by the combined disk test. A significant increase in the inhibition zone diameter of meropenem was observed in plates with the tested drugs compared to control plates. *: p < 0.05 and ***: p < 0.001.
FIGURE 3
FIGURE 3
Inhibition of carbapenemase by pantoprazole and captopril. The sub-minimum inhibitory concentration of pantoprazole showed higher inhibiting activities than that of captopril. ***: p < 0.001.
FIGURE 4
FIGURE 4
Downregulation of (A) bla NDM and (B) bla VIM genes by pantoprazole. Pantoprazole downregulated the expression of both genes. ***: p < 0.001.
FIGURE 5
FIGURE 5
Putative binding modes of compounds pantoprazole (upper panel), captopril (middle panel), and meropenem (lower panel) with the receptor pocket of apo New Delhi metallo-β-lactamase-1 (NDM-1) crystal structure (Protein Data Bank (PDB) ID: 3SPU).
FIGURE 6
FIGURE 6
Putative binding modes of pantoprazole (upper panel), captopril (middle panel), and meropenem (lower panel) with the receptor pocket of the Verona integron-encoded MBL-2 (VIM-2) crystal structure (PDB ID: 5YD7).
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