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

The MIC of 22 tamoxifen derivatives was determined againstS. aureusreference 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 derivatives2,5, and6reduced dose-dependently the growth of the USA7 strain. Moreover, treatment of MRSA with derivatives2and5resulted 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 MIC₅₀values 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.