Antibacterial activity of tamoxifen derivatives against methicillin-resistant Staphylococcus aureus

  1. Irene Molina Panadero
  2. Javier Falcón Torres
  3. Karim Hmadcha
  4. Salvatore Princiotto
  5. Luigi Cutarella
  6. Mattia Mori
  7. Sabrina Dallavalle
  8. Michael S. Christodoulou
  9. Younes Smani

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Abstract

The present work aimed to discover new tamoxifen derivatives with antimicrobial potential, particularly targeting methicillin-resistant Staphylococcus aureus (MRSA).

The MIC of 22 tamoxifen derivatives was determined against S. aureus reference and MRSA strains, using microdilution assays. The antibacterial effects of selected tamoxifen derivatives against MRSA (USA7) were assessed through bacterial growth assays. Bacterial membrane permeability and molecular docking assays were performed.

The MIC of the tamoxifen derivatives against MRSA ranged from to 16 to >64 μg/mL. Bacterial growth assays demonstrated that tamoxifen derivatives 2 , 5 , and 6 reduced dose-dependently the growth of the USA7 strain. Moreover, treatment of MRSA with derivatives 2 and 5 resulted in increased membrane permeabilization without being the cell wall their molecular target.

These data suggest that tamoxifen derivatives exhibit antibacterial activity against MRSA, potentially broadening the spectrum of available drug treatments for combating antimicrobial-resistant Gram-positive bacteria.

Importance

The development of new antimicrobial therapeutic strategies requires immediate attention to avoid the tens of millions of deaths predicted to occur by 2050 as a result of multidrug-resistant (MDR) bacterial infections. In this study, we assessed the antibacterial activity of 22 tamoxifen derivatives against methicillin-resistant Staphylococcus aureus (MRSA). We found that three tamoxifen derivatives exhibited antibacterial activity against MRSA clinical isolats, presenting MIC 50 values between 16 and 64 μg/mL and reducing bacterial growth over 24 h. Additionally, this antibacterial activity for two of the derivatives was accompanied by increased membrane permeability of MRSA. Our results suggest that tamoxifen derivatives might be used as a potential therapeutic alternative for treating MRSA strains in an animal model of infection.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/13008200.

    Review for : Antibacterial activity of tamoxifen derivatives against methicillin-resistant Staphylococcus aureus

    by Aniket Sharma1,# and Nikhil Srivastava1,#

    1Department of Animal Science, University of Wyoming, USA

    #Contributed equally

    1. Line 35: The term "microdilution assay" should be corrected to "microbroth dilution assay."

    2. Line 57: The word "isolates" is misspelled.

    3. Line 70: A reference is missing.

    4. Materials and Methods Section: There are crucial details missing about the isolation procedure and the source of the isolates. Additionally, there is no information about ethical clearance for these clinical samples.

    5. Line 235: The correct term should be "Luria-Bertani broth."

    6. MIC Controls: The rationale behind using P. aeruginosa as a positive control needs to be provided, information regarding negative control, solvent control for the Minimum Inhibitory Concentration (MIC) assay is missing.

    8. MIC Analysis: Information regarding how the MIC results were analyzed, whether spectrophotometrically or dye-based, is missing.

    9. Bacterial Growth Curve: The reason for using a 1/200 dilution for making the bacterial growth curve should be explained.

    10. Membrane Permeability Assay: The starting concentration of cells is not mentioned.

    11. Fluorescence Monitoring: The use of fluorescence monitoring with a Typhoon FLA scanner in the membrane permeability assay should be explained in more detail.

    12. Alternative Methods: Consider using spectrophotometry as an alternate method for measuring fluorescence.

    13. Negative Control for Membrane Permeability: There should be a negative control in the membrane permeability assay that is expected to show increased fluorescence at MIC levels.

    14. MDS Data: Information about the molecular dynamic simulation (MDS) data with derivative 2 is missing.

    1. In general, there are multiple spelling and grammatical errors which should be addressed.

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2024.07.16.603795v1 on bioRxiv