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Introduction <p>Multidrug-resistant (MDR) <i>Staphylococcus aureus</i>, <i>Pseudomonas aeruginosa</i>, and <i>Candida albicans</i> threaten treatment success, particularly in resource-limited settings. Repurposing licensed, inexpensive non-antibiotic drugs may provide a strategy for enhancing the activity of established antimicrobial agents.</p> Methods <p>Clinical isolates from Sana’a, Yemen, and American Type Culture Collection (ATCC) reference strains were tested in vitro with amlodipine, fluoxetine, and escitalopram, individually and in dual or triple combinations with ciprofloxacin or fluconazole. Antimicrobial activity was evaluated using agar-well diffusion, broth microdilution minimum inhibitory concentration (MIC), minimum bactericidal or fungicidal concentration (MBC/MFC), and checkerboard fractional inhibitory concentration index (FICI) assays. Molecular docking with AutoDock Vina was used to explore plausible interactions with MurB (PDB 1HSK), LasR (PDB 3IX3), and CYP51 (PDB 5V5Z). Normal mode analysis (NMA) with iMODS was performed for selected fluoxetine–LasR and fluoxetine–MurB complexes as a preliminary structural-dynamics assessment.</p> Results <p>Fluoxetine produced inhibition zones of at least 27&#xa0;mm across the tested organisms. Amlodipine produced larger zones against <i>S. aureus</i> and <i>C. albicans</i> than against <i>P. aeruginosa</i>, whereas escitalopram produced smaller zones overall. Checkerboard testing identified synergy (FICI ≤ 0.50) for selected combinations. Selected triple combinations reduced MIC values by 4- to 64-fold. The largest diffusion readouts were observed with ciprofloxacin + fluoxetine + amlodipine against <i>S. aureus</i> (101&#xa0;mm), ciprofloxacin + fluoxetine + escitalopram against <i>P. aeruginosa</i> (88.5&#xa0;mm), and ciprofloxacin + amlodipine + fluconazole against <i>C. albicans</i> (138.5&#xa0;mm). Docking scores and NMA outputs provided hypothesis-generating structural context for the experimental findings.</p> Conclusions <p>Antimicrobial enhancement was combination- and organism-dependent. Selected combinations showed checkerboard-defined synergy, whereas diffusion assays were interpreted as screening outcomes only. Docking and NMA findings were supportive and hypothesis-generating but did not establish target engagement or mechanism.</p>

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Repurposing amlodipine, fluoxetine, and escitalopram as non-antibiotic adjuvants: in vitro enhancement of ciprofloxacin and fluconazole activity against multidrug-resistant bacterial and candida clinical isolates

  • 期刊论文

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  • 发表日期：

    2026年7月23日

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  • Mohammed A. Alkhawlani,
  • Wafa M. Al-Madhagi,
  • Mahmoud Mahyoob Alburyhi,
  • Ali Gamal Al-kaf,
  • Maged Al-Najar

摘要

Introduction

Multidrug-resistant (MDR) Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans threaten treatment success, particularly in resource-limited settings. Repurposing licensed, inexpensive non-antibiotic drugs may provide a strategy for enhancing the activity of established antimicrobial agents.

Methods

Clinical isolates from Sana’a, Yemen, and American Type Culture Collection (ATCC) reference strains were tested in vitro with amlodipine, fluoxetine, and escitalopram, individually and in dual or triple combinations with ciprofloxacin or fluconazole. Antimicrobial activity was evaluated using agar-well diffusion, broth microdilution minimum inhibitory concentration (MIC), minimum bactericidal or fungicidal concentration (MBC/MFC), and checkerboard fractional inhibitory concentration index (FICI) assays. Molecular docking with AutoDock Vina was used to explore plausible interactions with MurB (PDB 1HSK), LasR (PDB 3IX3), and CYP51 (PDB 5V5Z). Normal mode analysis (NMA) with iMODS was performed for selected fluoxetine–LasR and fluoxetine–MurB complexes as a preliminary structural-dynamics assessment.

Results

Fluoxetine produced inhibition zones of at least 27 mm across the tested organisms. Amlodipine produced larger zones against S. aureus and C. albicans than against P. aeruginosa, whereas escitalopram produced smaller zones overall. Checkerboard testing identified synergy (FICI ≤ 0.50) for selected combinations. Selected triple combinations reduced MIC values by 4- to 64-fold. The largest diffusion readouts were observed with ciprofloxacin + fluoxetine + amlodipine against S. aureus (101 mm), ciprofloxacin + fluoxetine + escitalopram against P. aeruginosa (88.5 mm), and ciprofloxacin + amlodipine + fluconazole against C. albicans (138.5 mm). Docking scores and NMA outputs provided hypothesis-generating structural context for the experimental findings.

Conclusions

Antimicrobial enhancement was combination- and organism-dependent. Selected combinations showed checkerboard-defined synergy, whereas diffusion assays were interpreted as screening outcomes only. Docking and NMA findings were supportive and hypothesis-generating but did not establish target engagement or mechanism.