Antibacterial activity of paroxetine against Staphylococcus aureus and possible mechanisms of action
Abstract
Aim: To evaluate the antibacterial activity of paroxetine alone and associated with oxacillin against isolates of methicillin-sensitive and -resistant Staphylococcus aureus. Materials & methods: The broth microdilution and checkerboard techniques were used, with investigation of possible mechanisms of action through flow cytometry, fluorescence microscopy and molecular docking, in addition to scanning electron microscopy for morphological analysis. Results: Paroxetine showed a MIC of 64 μg/ml and bactericidal activity, mostly additive interactions in combination with oxacillin, evidence of action on genetic material and membrane, morphological changes in microbial cells and influence on virulence factors. Conclusion: Paroxetine has antibacterial potential from the perspective of drug repositioning.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Methicillin-resistant Staphylococcus aureus: an update on the epidemiology, treatment options and infection control. Curr. Med. Res. Pract. 8(1), 18–24 (2018).
- 2. . Methicillin-resistant Staphylococcus aureus: molecular characterization, evolution, and epidemiology. Clin. Microbiol. Rev. 31(4), e00020-18 (2018).
- 3. Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research. Nat. Rev. Microbiol. 17(4), 203–218 (2019).
- 4. . Characterisation of community-acquired Staphylococcus aureus causing skin and soft tissue infections in a children’s hospital in Shanghai, China. Epidemiol. Infect. 147, e323 (2019).
- 5. . 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).
- 6. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18(3), 318–327 (2018). • MRSA belongs to the WHO high-priority list for research and development of new antibiotics.
- 7. . A review of computational drug repositioning: strategies, approaches, opportunities, challenges, and directions. J. Cheminform. 12(1), 46 (2020).
- 8. Non-antibiotic drug repositioning as an alternative antimicrobial approach. Antibiotics 11(6), 816 (2022).
- 9. . Drug repurposing for antimicrobial discovery. Nat. Microbiol. 4(4), 565–577 (2019).
- 10. . Paroxetine: a review. CNS Drug Rev. 7(1), 25–47 (2001).
- 11. Repositioning of fluoxetine and paroxetine: study of potential antibacterial activity and its combination with ciprofloxacin. Med. Chem. Res. 29(3), 556–563 (2020).
- 12. Repositioning of antidepressant drugs and synergistic effect with ciprofloxacin against multidrug-resistant bacteria. World J. Microbiol. Biotechnol. 37(3), 53 (2021).
- 13. . Antimicrobial properties of various psychotropic drugs against broad range microorganisms. Curr. Psychopharmacol. 3(3), 195–202 (2014).
- 14. . Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int. J. Antimicrob. Agents 14(3), 177–180 (2000).
- 15. . Repositioning of non-antibiotic drugs as an alternative to microbial resistance: a systematic review. Int. J. Antimicrob. Agents 58(3), 106380 (2021). •• Antibacterial activity of paroxetine reported in the literature.
- 16. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing (31st ed.). CLSI supplement M100. Clinical and Laboratory Standards Institute, PA, USA (2021).
- 17. Etomidate inhibits the growth of MRSA and exhibits synergism with oxacillin. Future Microbiol. 15(17), 1611–1619 (2020).
- 18. Synergistic activity of diclofenac sodium with oxacillin against planktonic cells and biofilm of methicillin-resistant Staphylococcus aureus strains. Future Microbiol. 16(6), 375–387 (2021).
- 19. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10. Clinical and Laboratory Standards Institute, PA USA (2015).
- 20. A mechanistic approach to the in-vitro resistance modulating effects of fluoxetine against meticillin resistant Staphylococcus aureus strains. Microb. Pathog. 127(August 2017), 335–340 (2019). • Fluoxetine, a selective serotonin reuptake inhibitor, also acts against MRSA through membrane damage and DNA fragmentation.
- 21. Eugenol provokes ROS-mediated membrane damage-associated antibacterial activity against clinically isolated multidrug-resistant Staphylococcus aureus strains. Infect. Dis. Res. Treat. 9, IDRT.S31741 (2016).
- 22. . Synergy, antagonism, and what the chequerboard puts between them. J. Antimicrob. Chemother. 52(1), 1 (2003).
- 23. . 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).
- 24. . Limits of propidium iodide as a cell viability indicator for environmental bacteria. Cytometry A 71(8), 592–598 (2007).
- 25. Distinguishing between living and nonliving bacteria: evaluation of the vital stain propidium iodide and its combined use with molecular probes in aquatic samples. J. Microbiol. Methods 32(3), 225–236 (1998).
- 26. . Antibiotic-induced bacterial cell death exhibits physiological and biochemical hallmarks of apoptosis. Mol. Cell 46(5), 561–572 (2012).
- 27. . MarvinSketch and MarvinView: molecule applets for the world wide web (2019). https://chemaxon.com/blog/presentation/marvinsketch-and-marvinview-molecule-applets-for-the-world-wide-web
- 28. ChemAxon. ‘Marvinafull featured chemical editor for making science accessible on all platforms’ (2019). https://chemaxon.com/marvin
- 29. . Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 4, 17 (2012).
- 30. . Bacterial targets of antibiotics in methicillin-resistant Staphylococcus aureus. Antibiotics 10(4), 398 (2021).
- 31. . Multiple ways to kill bacteria via inhibiting novel cell wall or membrane targets. Future Med. Chem. 12(13), 1253–1279 (2020).
- 32. Activity of arginine–phenylalanine and arginine–tryptophan-based surfactants against Staphylococcus aureus. Future Microbiol. 17(17), 1363–1379 (2022).
- 33. Anti-MRSA activity of curcumin in planktonic cells and biofilms and determination of possible action mechanisms. Microb. Pathog. 155, 104892 (2021).
- 34. Crystal structure of FtsA from Staphylococcus aureus. FEBS Lett. 588(10), 1879–1885 (2014).
- 35. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim.. Proteins 76(3), 706–717 (2009).
- 36. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466(7309), 935–940 (2010).
- 37. Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents – SAR of left-hand-side moiety (Part 2). Bioorg. Med. Chem. Lett. 25(9), 1831–1835 (2015).
- 38. Symmetric bis-benzimidazoles: new sequence-selective DNA-binding molecules. Chem. Commun. (10), 929–930 (1999).
- 39. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 319(5868), 1391–1394 (2008).
- 40. Targeting mannitol metabolism as an alternative antimicrobial strategy based on the structure–function study of mannitol-1-phosphate dehydrogenase in Staphylococcus aureus. MBio 10(4), e02660-18 (2019).
- 41. Crystal structure of leucotoxin S component: new insight into the staphylococcal beta-barrel pore-forming toxins. J. Biol. Chem. 279(39), 41028–41037 (2004).
- 42. Mechanism of action and in vivo efficacy of a human-derived antibody against Staphylococcus aureus alpha-hemolysin. J. Mol. Biol. 425(10), 1641–1654 (2013).
- 43. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc. Natl Acad. Sci. USA 110(42), 16808–16813 (2013).
- 44. Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors. Protein Sci. 10(10), 2008–2016 (2001).
- 45. . AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31(2), 455–461 (2009).
- 46. Virtual screening based on molecular docking of possible inhibitors of Covid-19 main protease. Microb. Pathog. 148, 104365 (2020).
- 47. UCSF Chimera – a visualization system for exploratory research and analysis. J. Comput. Chem. 25(13), 1605–1612 (2004).
- 48. . Discovery Studio Modeling Environment, Release 2017, San Diego (2016).
- 49. . The PyMOL Molecular Graphics System, Version 2.3 (2020).
- 50. Evaluation of the antifungal effect of chlorogenic acid against strains of Candida spp. resistant to fluconazole: apoptosis induction and in silico analysis of the possible mechanisms of action. J. Med. Microbiol. 71(5), 1–17 (2022).
- 51. Effects of ketamine in methicillin-resistant Staphylococcus aureus and in silico interaction with sortase A. Can. J. Microbiol. 67(12), 885–893 (2021).
- 52. Antifungal activity of etomidate against growing biofilms of fluconazole-resistant Candida spp. strains, binding to mannoproteins and molecular docking with the ALS3 protein. J. Med. Microbiol. 69(10), 1221–1227 (2020).
- 53. . Defining and combating antibiotic resistance from One Health and Global Health perspectives. Nat. Microbiol. 4(9), 1432–1442 (2019).
- 54. . Clinical and economic impact of antibiotic resistance in developing countries: a systematic review and meta-analysis. PLOS ONE 12(12), e0189621 (2017).
- 55. Alternatives for the treatment of infections caused by ESKAPE pathogens. J. Clin. Pharm. Ther. 45(4), 863–873 (2020).
- 56. Drug repositioning: progress and challenges in drug discovery for various diseases. Eur. J. Med. Chem. 234, 114239 (2022).
- 57. . Antimicrobial activity of three Baccharis species used in the traditional medicine of Northern Chile. Molecules 13(4), 790–794 (2008).
- 58. . Drug combination therapy increases successful drug repositioning. Drug Discov. Today 21(7), 1189–1195 (2016).
- 59. . Ciprofloxacin: in vitro activity, mechanism of action, and resistance. Rev. Infect. Dis. 10(3), 516–527 (1988).
- 60. . Investigating the molecular mechanism of staphylococcal DNA gyrase inhibitors: a combined ligand-based and structure-based resources pipeline. J. Mol. Graph. Model. 85, 122–129 (2018).
- 61. . Computational approaches to develop isoquinoline based antibiotics through DNA gyrase inhibition mechanisms unveiled through antibacterial evaluation and molecular docking. Mol. Inform. 37(12), e1800048 (2018).
- 62. . An overview of apoptosis assays detecting DNA fragmentation. Mol. Biol. Rep. 45(5), 1469–1478 (2018).
- 63. . Red but not dead? Membranes of stressed Saccharomyces cerevisiae are permeable to propidium iodide. Environ. Microbiol. 13(1), 163–171 (2011).
- 64. . Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry 27(1), 1–20 (1997).
- 65. . Aminoacyl-tRNA synthetases: essential and still promising targets for new anti-infective agents. Expert Opin. Investig. Drugs 16(5), 573–593 (2007).
- 66. . Dual inhibition of S. aureus TyrRS and S. aureus gyrase by two 4-amino-4′-acetyldiphenyl sulfide-based Schiff bases: structural features, DFT study, Hirshfeld surface analysis and molecular docking. Inorg. Chem. Commun. 143(July), 109779 (2022).
- 67. . Tyrosyl-tRNA synthetase inhibitors: a patent review. Expert Opin. Ther. Pat. 27(5), 557–564 (2017).
- 68. . Transdermal drug delivery of paroxetine through lipid-vesicular formulation to augment its bioavailability. Int. J. Pharm. 443(1-2), 307–317 (2013).
- 69. In vitro anti-Candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates. Microb. Pathog. 107, 341–348 (2017). •• Paroxetine does not show cytotoxicity in L929 cells after 72 h of exposure (IC50 > 100 μg/ml).
- 70. . Commensal staphylococci influence Staphylococcus aureus skin colonization and disease. Trends Microbiol. 27(6), 497–507 (2019).
- 71. . Celastrol mitigates staphyloxanthin biosynthesis and biofilm formation in Staphylococcus aureus via targeting key regulators of virulence; in vitro and in vivo approach. BMC Microbiol. 22(1), 106 (2022).
- 72. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J. Exp. Med. 202(2), 209–215 (2005).
- 73. . Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int. J. Antimicrob. Agents 22(3), 254–261 (2003).
- 74. . Synthesis and evaluation of PSSRI-based inhibitors of Staphylococcus aureus multidrug efflux pumps. Bioorganic Med. Chem. Lett. 18(4), 1368–1373 (2008).
- 75. Evolution from a natural flavones nucleus to obtain 2-(4-propoxyphenyl) quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. J. Med. Chem. 54(16), 5722–5736 (2011).
- 76. . Inhibition of drug efflux pumps in Staphylococcus aureus: current status of potentiating existing antibiotics. Future Microbiol. 8(4), 491–507 (2013).