The promising anti-virulence activity of candesartan, domperidone, and miconazole on Staphylococcus aureus
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Amira M El-Ganiny1, Amany I Gad2, Mona A El-Sayed1
1Microbiology and Immunology Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Abstract:
Staphylococcus aureus is a primary cause of hospital and community-acquired infections. With the emergence of multidrug-resistant S. aureus strains, there is a need for new drugs discovery. Due to the poor supply of new antimicrobials, targeting virulence of S. aureus may generate weaker selection for resistant strains, anti-virulence agents disarm the pathogen instead of killing it. In this study, the ability of the FDA-approved drugs domperidone, candesartan, and miconazole as inhibitors of S. aureus virulence was investigated. The effect of tested drugs was evaluated against biofilm formation, lipase, protease, hemolysin, and staphyloxanthin production by using phenotypic and genotypic methods. At sub-inhibitory concentrations, candesartan, domperidone, and miconazole showed a significant inhibition of hemolysin (75.8-96%), staphyloxanthin (81.2-85%), lipase (50-65%), protease (40-64%), and biofilm formation (71.4-90%). Domperidone and candesartan have similar activity and were more powerful than miconazole against S. aureus virulence. The hemolysins and lipase inhibition were the greatest under the domperidone effect. Candesartan showed a remarkable reduction in staphyloxanthin production. The highest inhibitory effect of proteolytic activity was obtained with domperidone and candesartan. Biofilm was significantly reduced by miconazole. Expression levels of crtM, sigB, sarA, agrA, hla, fnbA, and icaA genes were significantly reduced under candesartan (68.98-82.7%), domperidone (62.6-77.2%), and miconazole (32.96-52.6%) at sub-MIC concentrations. Candesartan showed the highest inhibition activity against crtM, sigB, sarA, agrA, hla, and icaA expression followed by domperidone then miconazole. Domperidone showed the highest downregulation activity against fnbA gene. In conclusion, candesartan, domperidone, and miconazole could serve as anti-virulence agents for attenuation of S. aureus pathogenicity.
Insights
This study explored FDA-approved drugs domperidone, candesartan, and miconazole as novel anti-virulence agents against Staphylococcus aureus infections. These drugs significantly reduced bacterial virulence factors and biofilm formation, offering a promising strategy against multidrug-resistant strains.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Staphylococcus aureus is a major cause of hospital and community-acquired infections.
- The rise of multidrug-resistant strains necessitates novel therapeutic strategies beyond traditional antibiotics.
- Targeting bacterial virulence factors offers an alternative approach to combat infections with potentially reduced selective pressure for resistance.
Purpose of the Study:
- To investigate the anti-virulence potential of FDA-approved drugs: domperidone, candesartan, and miconazole against Staphylococcus aureus.
- To evaluate the efficacy of these drugs in inhibiting key virulence factors and biofilm formation.
- To assess the impact of these drugs on the expression of relevant virulence genes.
Main Methods:
- Phenotypic and genotypic methods were employed to evaluate drug effects.
- Assays included measurements of hemolysin, lipase, protease, staphyloxanthin production, and biofilm formation.
- Gene expression analysis was performed for virulence-related genes (crtM, sigB, sarA, agrA, hla, fnbA, icaA) at sub-inhibitory concentrations.
Main Results:
- Domperidone, candesartan, and miconazole significantly inhibited S. aureus virulence factors and biofilm formation at sub-inhibitory concentrations.
- Candesartan and domperidone demonstrated potent inhibition of hemolysin, staphyloxanthin, lipase, and protease production, while miconazole was most effective against biofilm formation.
- All tested drugs significantly downregulated the expression of key virulence genes, with candesartan showing the broadest and strongest inhibitory effect.
Conclusions:
- Domperidone, candesartan, and miconazole exhibit significant anti-virulence properties against Staphylococcus aureus.
- These repurposed drugs represent promising candidates for developing novel anti-virulence therapies to combat S. aureus pathogenicity.
- Targeting virulence factors with these agents could offer a valuable strategy in managing infections caused by multidrug-resistant S. aureus.
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