Activity of amlodipine against Staphylococcus aureus: association with oxacillin and mechanism of action
Abstract
Aim: This study was designed to evaluate the in vitro antimicrobial activity of amlodipine against Staphylococcus aureus strains. Materials & methods: The antimicrobial activity of amlodipine was evaluated by the broth microdilution method and its interaction with oxacillin was evaluated by checkerboard assay. The possible mechanism of action was evaluated by flow cytometry and molecular docking techniques. Results: Amlodipine showed activity against S. aureus between 64 and 128 μg/ml, in addition to showing synergism in approximately 58% of the strains used. Amlodipine also showed good activity against forming and mature biofilms. The possible mechanism of action may be attributed to its ability to lead to cell death. Conclusion: Amlodipine has antibacterial activity against S. aureus.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. WHO publishes list of bacteria for which new antibiotics are urgently needed. www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed
- 2. . Twenty-year trends in antimicrobial susceptibilities among Staphylococcus aureus from the SENTRY Antimicrobial Surveillance Program. Open Forum Infect. Dis. 6(Suppl. 1), S47–S53 (2019).
- 3. Characterisation of antibiotic resistance, virulence, clonality and mortality in MRSA and MSSA bloodstream infections at a tertiary-level hospital in Hungary: a 6-year retrospective study. Ann. Clin. Microbiol. Antimicrob. 19(1), 17 (2020).
- 4. Penicillin susceptibility among invasive MSSA infections: a multicentre study in 16 Spanish hospitals. J. Antimicrob. Chemother. 76(10), 2519–2527 (2021).
- 5. . Is MRSA more virulent than MSSA? Clin. Microbiol. Infect. 13(9), 843–845 (2007).
- 6. . Methicillin-resistant Staphylococcus aureus: molecular characterization, evolution, and epidemiology. Clin. Microbiol. Rev. 31(4), e00020–18 (2018).
- 7. . Staphylococcus aureus biofilms: recent developments in biofilm dispersal. Front. Cell Infect. Microbiol. 4, 178 (2014).
- 8. . New antibiotics for the treatment of infections by multidrug-resistant microorganisms. Med. Clin. (Barc.) 154(9), 351–357 (2020).
- 9. . Drug repurposing for antimicrobial discovery. Nat. Microbiol. 4(4), 565–577 (2019).
- 10. . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58(3), 621–681 (2006).
- 11. . Amlodipine (2020). www.ncbi.nlm.nih.gov/books/NBK519508/
- 12. In vitro activity of calcium channel blockers in combination with conventional antifungal agents against clinically important filamentous fungi. Acta Biol. Hung. 68(3), 334–344 (2017).
- 13. . Synergistic effect of fluconazole and calcium channel blockers against resistant Candida albicans. PLOS ONE 11(3), e015085 (2016).
- 14. . Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: scope and hope for the future. Int. J. Antimicrob. Agents 36(4), 295–302 (2010). •• According to the authors, amlodipine is the most promising nonantibiotic antimicrobial cardiovascular drug. This study suggested that the doses of amlodipine needed to effectively treat an infection in vivo may be significantly lower than the doses used in vitro to inhibit bacterial growth.
- 15. . Estimation of antimicrobial activity of selected non-antibiotic products. Acta Pol. Pharm. 63(5), 457–460 (2006).
- 16. M07-A10 Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Tenth Edition (2015). https://clsi.org/media/1928/m07ed11_sample.pdf
- 17. A mechanistic approach to the in-vitro resistance modulating effects of fluoxetine against meticillin resistant Staphylococcus aureus strains. Microb. Pathog. 127, 335–340 (2019).
- 18. Eugenol provokes ROS-mediated membrane damage-associated antibacterial activity against clinically isolated multidrug-resistant Staphylococcus aureus strains. Infect. Dis. 9, PMC4756864 (2016).
- 19. . Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52(1), 1 (2003).
- 20. . Searching for new strategies against biofilm infections: colistin-AMP combinations against Pseudomonas aeruginosa and Staphylococcus aureus single- and double-species biofilms. PLOS ONE 12(3), e0174654 (2017).
- 21. . Anti-biofilm activity against Staphylococcus aureus MRSA and MSSA of neolignans and extract of Piper regnellii. Rev. Bras. Farmacogn. 27(1), 112–117 (2017).
- 22. . A comprehensive study into the impact of a chitosan mouthwash upon oral microorganism's biofilm formation in vitro. Carbohydr. Polym. 101(1), 1081–1086 (2014).
- 23. . Anti-biofilm activity against Staphylococcus aureus MRSA and MSSA of neolignans and extract of Piper regnellii. Rev. Bras. Farmacogn. 27(1), 112–117 (2017).
- 24. Etomidate inhibits the growth of MRSA and exhibits synergism with oxacillin. Future Microbiol. 15(17), 1611–1619 (2020).
- 25. . Coriander (Coriandrum sativum L.) essential oil: its antibacterial activity and mode of action evaluated by flow cytometry. J. Med. Microbiol. 60(Pt 10), 1479–1486 (2011).
- 26. . Limits of propidium iodide as a cell viability indicator for environmental bacteria. Cytometry A 71(8), 592–598 (2007).
- 27. Screening of antimicrobial metabolite yeast isolates derived biome Ceará against pathogenic bacteria, including MRSA: antibacterial activity and mode of action evaluated by flow cytometry. Int. J. Curr. Microbiol. App. Sci. 4(5), 459–472 (2015).
- 28. Antifungal activity of naphthoquinoidal compounds in vitro against fluconazole-resistant strains of different Candida species: a special emphasis on mechanisms of action on Candida tropicalis. PLOS ONE 9(5), e93698 (2014).
- 29. . Antibiotic-induced bacterial cell death exhibits physiological and biochemical hallmarks of apoptosis. Mol. Cell 46(5), 561–572 (2012).
- 30. MarvinSketch and MarvinView: Molecule Applets for the World Wide Web. ChemAxon. https://chemaxon.com/presentation/marvinsketch-and-marvinview-molecule-applets-for-the-world-wide-web
- 31. Marvin. ChemAxon. https://chemaxon.com/products/marvin
- 32. . Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 4(8), 1–17 (2012).
- 33. Anti-MRSA activity of curcumin in planktonic cells and biofilms and determination of possible action mechanisms. Microb. Pathog. 155, 104892 (2021).
- 34. Mechanism of action and in vivo efficacy of a human-derived antibody against Staphylococcus aureus α-hemolysin. J. Mol. Biol. 425(10), 1641–1654 (2013).
- 35. Effectiveness of alpha-toxin Fab monoclonal antibody therapy in limiting the pathology of Staphylococcus aureus keratitis. Ocul. Immunol. Inflamm. 23(4), 297–303 (2015).
- 36. . α-Glucosidase inhibition by luteolin: kinetics, interaction and molecular docking. Int. J. Biol. Macromol. 64, 213–223 (2014).
- 37. Using AutoDock 4 and AutoDock Vina with AutoDockTools: A Tutorial. https://zdoc.pub/using-autodock-4-and-autodock-vina-with-autodocktools-a-tuto.html
- 38. . AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem. 31(2), 455 (2010).
- 39. Virtual screening based on molecular docking of possible inhibitors of COVID-19 main protease. Microb. Pathog. 148, 104365 (2020).
- 40. BIOVIA Discovery Studio–BIOVIA–Dassault Systèmes®. www.3ds.com/products-services/biovia/products/molecular-modeling-simulation/biovia-discovery-studio/
- 41. UCSF Chimera–a visualization system for exploratory research and analysis. J. Comput. Chem. 25(13), 1605–1612 (2004).
- 42. . An alternative method for the evaluation of docking performance: RSR vs RMSD. J. Chem. Inf. Model 48(7), 1411–1422 (2008).
- 43. . In silico predictive model to determine vector-mediated transport properties for the blood-brain barrier choline transporter. Adv. Appl. Bioinform. Chem. 7(1), 23 (2014).
- 44. . Molecular modelling of protein-carbohydrate interactions. Docking of monosaccharides in the binding site of concanavalin A. Glycobiology 1(6), 631–642 (1991).
- 45. . An overview of drug discovery and development. Future Med. Chem. 12(10), 939–947 (2020).
- 46. VanZwieten PA.Amlodipine: an overview of its pharmacodynamic and pharmacokinetic properties.17(9 Suppl. 3), III3–III6 (1994). https://pubmed.ncbi.nlm.nih.gov/9156957/
- 47. Pharmacodynamic (hemodynamic) and pharmacokinetic comparisons of S-amlodipine gentisate and racemate amlodipine besylate in healthy Korean male volunteers: two double-blind, randomized, two-period, two-treatment, two-sequence, double-dummy, single-dose crossover studies. Clin. Ther. 32(1), 193–205 (2010).
- 48. . In vitro activity of non-antibiotic drugs against Staphylococcus aureus clinical strains. J. Glob. Antimicrob. Resist. 27, 167–171 (2021). •• Boyd et al. evaluate the minimum inhibitory and bactericidal concentrations of amlodipine against clinical strains of S. aureus and discuss the only metric for evaluating adequate drug exposure in a treatment.
- 49. . In vitro interactions of ambroxol hydrochloride or amlodipine in combination with antibacterial agents against carbapenem-resistant Acinetobacter baumannii. Lett. Appl. Microbiol. 70(3), 189–195 (2020).
- 50. . Evaluation of amlodipine inhibition and antimicrobial effects. Int. J. Pharm. Chem. 5(1), 12 (2019). • Yi shows, from enzymatic assays and bacterial tests, that amlodipine may serve as an auxiliary drug, considering that one of the mechanisms presented is the inhibition of β-lactamase, showing the synergistic activity of amlodipine with other beta-lactams.
- 51. . Antimicrobial activity of three Baccharis species used in the traditional medicine of Northern Chile. Molecules 13(4), 790 (2008).
- 52. . Biofilm-forming methicillin-resistant Staphylococcus aureus survive in Kupffer cells and exhibit high virulence in mice. Toxins (Basel) 8(7), 198 (2016).
- 53. . Antihypertensive, amlodipine besilate inhibits growth and biofilm of human fungal pathogen Candida. Assay Drug Dev. Technol. 14(5), 291–297 (2016).
- 54. . Microbiological appraisal of levofloxacin activity against Pseudomonas aeruginosa biofilm in combination with different calcium channel blockers in vitro. J. Chemother. 21(2), 135–143 (2009).
- 55. . Time to recognise that mitochondria are bacteria? Trends Microbiol. 19(2), 58–64 (2011).
- 56. . DNA gyrase and topoisomerase IV: biochemical activities, physiological roles during chromosome replication, and drug sensitivities. Biochim. Biophys. Acta 1400(1–3), 29–43 (1998).
- 57. . Mechanism of action of and resistance to quinolones. Microb. Biotechnol. 2(1), 40 (2009).
- 58. . Microbiological appraisal of levofloxacin activity against Pseudomonas aeruginosa biofilm in combination with different calcium channel blockers in vitro. J. Chemother. 21(2), 135–143 (2013).