Hexahydroacridine derivatives as novel anti-Salmonella agents: In vitro, In vivo, and In silico studies

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Faraag A.H.I.; Mahdy A.; Abdelmongy M.A.A.; Mahdy E.-S.M.; Abdel-Naby M.A.; Esmat A.; Tolba M.; Hammad S.F.; Khatab H.A.; Basiouny M.S.; Abdul-Baki E.A.; Nasr S.M.; Abdel-Hafez L.J.M.

Journal: Microbial Pathogenesis

Publisher: Academic Press

Publication Date: June 2026

Volume / Issue: Volume 215

Article No.: 108453

ISSN: 8824010

DOI: 10.1016/j.micpath.2026.108453

Scopus: View on Scopus

PubMed: 41871669

Document Type: Article

Authors and Affiliations

Faraag A.H.I., Botany and Microbiology Department, Faculty of Science, Helwan University, Cairo, Egypt, School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt; Mahdy A., School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt; Abdelmongy M.A.A., Biochemistry, Department of Chemistry, Faculty of Science, Helwan University, Egypt; Mahdy E.-S.M., Biochemistry, Department of Chemistry, Faculty of Science, Helwan University, Egypt; Abdel-Naby M.A., Department of Chemistry of Natural Products, National Research Center, Cairo, Egypt; Esmat A., Zoology & Entomology Dept., Faculty of Science, Helwan University, 11975, Egypt; Tolba M., Zoology & Entomology Dept., Faculty of Science, Helwan University, 11975, Egypt; Hammad S.F., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt, Basic and Applied Science Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, Alexandria, Egypt; Khatab H.A., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo, Egypt, Basic and Applied Science Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, Alexandria, Egypt; Basiouny M.S., School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt, Environmental Studies & Research Institute (ESRI) University of Sadat City Sadat City 32897 Menoufia Egypt; Abdul-Baki E.A., Genomic Signature Cancer Center, Next Generation Sequencer Unit, Tanta University Global Educational Hospital, Tanta University, Tanta, Egypt; Nasr S.M., School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt, Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Abdel-Hafez L.J.M., Microbiology and Immunology, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt

Abstract

AbstractThe rise of multidrug-resistant (MDR) Salmonella enterica presents a critical global health concern and highlights the need for new antibacterial agents. This study investigates the activity of the hexahydroacridine derivatives D01 and D04 using a comprehensive set of in vitro, in vivo, and in silico approaches. Both compounds exhibited strong bactericidal effects against MDR S. enterica, with D04 showing superior potency, achieving a ≥6 log10 reduction in CFU/mL within 24 h at 2 × MIC. D04 also reduced biofilm formation by 95% at 2 × MIC. Synergistic interactions with ciprofloxacin and tetracycline were observed for both derivatives. Serial passage experiments demonstrated stable MIC values, indicating minimal resistance development. In vivo assays using zebrafish and Galleria mellonella confirmed enhanced survival and decreased bacterial burden following treatment. Histopathological evaluation of murine intestinal tissue showed preserved epithelial integrity in treated groups. qPCR analysis revealed downregulation of virulence- and biofilm-associated genes and upregulation of stress response genes. Molecular docking studies further supported strong binding of D01 and D04 to the S. enterica InvA protein. Collectively, these results identify D01 and D04 as promising antibacterial and anti-virulence candidates with low resistance potential and favorable host compatibility. © 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Keywords

Antibacterial agents; Gut microbiota; Hexahydroacridine derivatives; Immunomodulation; Molecular docking; Salmonella enterica; Transcriptomic analysis; Animals; Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Ciprofloxacin; Computer Simulation; Drug Resistance, Multiple, Bacterial; Drug Synergism; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Moths; Salmonella Infections; Tetracycline; Virulence; Zebrafish; anti salmonella agent; antiinfective agent; chloramphenicol; gentamicin; hexahydroacridine derivative; kanamycin; nalidixic acid; streptomycin; sulfamethoxazole; trimethoprim; unclassified drug; bacterial protein; animal experiment; animal model; antibacterial activity; antibiotic sensitivity; Article; bacterial load; bacterial strain; bactericidal activity; bacterium identification; bacterium isolation; biofilm formation; Caco-2 cell line; colony forming unit; computer model; controlled study; cytotoxic concentration; cytotoxicity assay; differential gene expression; DNA extraction; down regulation; Galleria mellonella; gene amplification; gene sequence; HEK293 cell line; HEK293T cell line; histopathology; human; human cell; intestine flora; male; metagenomics; minimum inhibitory concentration; mouse; MTT assay; nonhuman; nucleotide sequence; operational taxonomic unit; oxidative stress; population growth estimation; preservation; real time polymerase chain reaction; Salmonella; serotyping; synergistic effect; transcriptomics; upregulation; zebra fish; animal; biofilm; chemistry; drug effect; drug potentiation; drug therapy; genetics; metabolism; microbial sensitivity test; microbiology; moth; multidrug resistance; salmonellosis

Citation Information

Scopus Citations: 1

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