Author(s):
Andrade, Mariana ; Neves, Joana ; Bento, Maria ; Marques, Joana ; Seabra, Sofia G. ; Silveira, Henrique ; Rodrigues, Liliana ; Armada, Ana ; Viveiros, Miguel ; Couto, Isabel ; Costa, Sofia Santos
Date: 2025
Persistent ID: http://hdl.handle.net/10362/182565
Origin: Repositório Institucional da UNL
Subject(s): antimicrobial resistance; biofilm; drug repurposing; efflux; infection model; Staphylococcus aureus; Microbiology; Biochemistry; Pharmacology, Toxicology and Pharmaceutics(all); Microbiology (medical); Infectious Diseases; Pharmacology (medical); SDG 3 - Good Health and Well-being
Description
Funding Information: This work was supported by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia (FCT, Portugal) through funds to GHTM\u2014UID/04413/2020, LA-REAL\u2014LA/P/0117/2020, to the Project DREBI, Ref. 2022.07931.PTDC (DOI: 10.54499/2022.07931.PTDC), to the grants of M.A. (UI/BD/154472/2022) and J.N. (2022.07931.PTDC), and to the contracts of J.M. (DOI: 10.54499/CEECIND/00450/2017/CP1415/CT0001), S.G.S. throught CEECINST/00102/2018/CP1567/CT0040 (DOI: 10.54499/CEECINST/00102/2018/CP1567/CT0040) and S.S.C. throught CEECINST/00042/2021/CP1773/CT0009 (DOI: 10.54499/CEECINST/00042/2021/CP1773/CT0009). Publisher Copyright: © 2025 by the authors.
Background/Objectives: Antimicrobial-resistant Staphylococcus aureus is a growing threat to human health for which alternative therapeutic options are needed. In this study, we aimed to evaluate the efficacy of amlodipine (AML) and imipramine (IMI) to treat S. aureus infection in the Galleria mellonella larval model by targeting efflux and biofilms, which are relevant contributors to antimicrobial resistance and virulence in S. aureus. Methods: In-house reared G. mellonella were used in virulence assays to determine the infective dose of two S. aureus strains differing in the expression of norA (gene encoding the native NorA efflux pump). Toxicology assays were conducted to determine the drugs’ LD50 for G. mellonella. Drug efficacy assays were performed to evaluate the potential of amlodipine, imipramine and the control drugs ciprofloxacin (CIP) and enalapril (ENA) to clear S. aureus infection in G. mellonella. Results: Survival analysis defined the infective dose as 1 × 107 CFU/larva for both strains. High LD50 values were determined (CIP: >1000 mg/kg; AML: >640 mg/kg; IMI: 1141 mg/kg; ENA: >1280 mg/kg), revealing a high tolerance of G. mellonella to these drugs. AML at 15 mg/kg and IMI at 100 mg/kg increased the larvae survival by 20% (p = 0.04) and 11% (p = 0.11), respectively, also positively affecting health score indexes. In agreement with the literature, ciprofloxacin at >100 mg/kg promoted larvae survival by >73%. Conclusions: Amlodipine and imipramine show mild potential as new therapeutic options for managing S. aureus infections but are promising as new lead molecules. This study also reinforces G. mellonella as a sustainable, reliable model for drug evaluation.
