Academic Journal
Sitagliptin attenuates urease-associated phenotypes and potentiates meropenem in multidrug-resistant Gram-negative clinical isolates: a preliminary repurposing study.
| Τίτλος: | Sitagliptin attenuates urease-associated phenotypes and potentiates meropenem in multidrug-resistant Gram-negative clinical isolates: a preliminary repurposing study. |
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| Συγγραφείς: | Eladl A; Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt., Abbas HA; Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt., Abd El-Hamid MI; Department of Microbiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt., Elbaramawi SS; Medicinal Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt., Noureldin NA; Medicinal Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt., Nazeih SI; Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. |
| Πηγή: | The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2026 Oct 06; Vol. 81 (11). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Oxford University Press Country of Publication: England NLM ID: 7513617 Publication Model: Print Cited Medium: Internet ISSN: 1460-2091 (Electronic) Linking ISSN: 03057453 NLM ISO Abbreviation: J Antimicrob Chemother Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1997- : London : Oxford University Press Original Publication: London, New York, Academic Press. |
| Ιατρικοί όροι (MeSH): | Anti-Bacterial Agents*/pharmacology , Thienamycins*/pharmacology , Thienamycins*/metabolism , Urease*/metabolism , Urease*/antagonists & inhibitors , Sitagliptin Phosphate*/pharmacology , Gram-Negative Bacteria*/drug effects , Gram-Negative Bacteria*/enzymology , Gram-Negative Bacteria*/isolation & purification , Enzyme Inhibitors*/pharmacology , Drug Resistance, Multiple, Bacterial*, Meropenem/pharmacology ; Animals ; Microbial Sensitivity Tests ; Drug Synergism ; Chlorocebus aethiops ; Humans ; Vero Cells ; Drug Repositioning ; Gene Expression Profiling ; Phenotype |
| Περίληψη: | Background: Urease contributes to urinary tract pathogenesis and catheter encrustation, whereas metallo-β-lactamases contribute to carbapenem resistance. Objectives: We investigated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates urease-associated phenotypes and potentiates meropenem against selected multidrug-resistant Gram-negative clinical isolates. Methods: Urease-associated activity was assessed in whole-cell suspensions and crude lysates of Proteus mirabilis. Alkalinization, crystal formation in artificial urine, and catheter-associated total biomass were also examined. Meropenem potentiation was evaluated by combined-disk and chequerboard assays, and meropenem-hydrolyzing activity was measured. Relative transcript abundance was assessed by quantitative reverse-transcription PCR, and docking was used to generate structural hypotheses. Vero-cell metabolic activity was evaluated by the MTT assay. Results: Sitagliptin (2000 µg/mL; one-eighth of its MIC) inhibited urease-associated assay signal by 53.2%-55.2% in whole-cell suspensions and crude lysates, reduced the urease-driven pH increase from 9.21 to 7.34 after 24 h, and reduced crystal-violet-stained catheter-associated biomass by 83.6%. It reduced the apparent meropenem hydrolysis signal in periplasmic extracts by 33%-55% and reduced meropenem MICs by 16- to 64-fold in combination assays, with FICI values of 0.1406-0.1875. In the Vero-cell assay, viability at 2000 µg/mL was 94.4%, and a 50% reduction in viability was not observed within the tested range. Sitagliptin exposure was associated with reduced relative transcript abundance of ureR, ureC, blaNDM, blaIMP, and blaVIM. Docking generated binding poses near catalytic metal centres. Conclusions: In the tested preparations and isolate panel, sitagliptin attenuated urease-associated phenotypes, reduced apparent meropenem-hydrolyzing activity and potentiated meropenem, supporting its further investigation as a potential anti-virulence and antibiotic-adjuvant candidate. (© The Author(s) 2026. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| Substance Nomenclature: | FV9J3JU8B1 (Meropenem) 0 (Anti-Bacterial Agents) 0 (Thienamycins) EC 3.5.1.5 (Urease) TS63EW8X6F (Sitagliptin Phosphate) 0 (Enzyme Inhibitors) |
| Entry Date(s): | Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261016 |
| Update Code: | 20261016 |
| DOI: | 10.1093/jac/dkag344 |
| PMID: | 42885748 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1460-2091 |
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| DOI: | 10.1093/jac/dkag344 |