Identification of a New FtsZ Inhibitor by Virtual Screening, Mechanistic Insights, and Structure–Activity Relationship Analyses

Antimicrobial resistance (AMR) poses a major threat to human health globally. Approximately 5 million deaths were attributed to AMR in 2019, and this figure is predicted to worsen, reaching 10 million deaths by 2050. In the search for new compounds that can tackle AMR, FtsZ inhibitors represent a valuable option. In the present study, a structure-based virtual screening is reported, which led to the identification of derivative <b>C11</b> endowed with an excellent minimum inhibitory concentration value of 2 μg/mL against Staphylococcus aureus. Biochemical assays clarified that compound <b>C11</b> targets FtsZ by inhibiting its polymerization process. <b>C11</b> also showed notable antimicrobial activity against <i>S. aureus</i> cystic fibrosis isolates and methicillin-resistant <i>S. aureus</i> strains. Derivative <b>C11</b> did not show cytotoxicity, while it had a synergistic effect with methicillin. <b>C11</b> also showed increased survival in the Galleria mellonella infection model. Lastly, structure-activity relationship and binding mode analyses were reported.