2. Academic Validation
  3. Identification of a New FtsZ Inhibitor by Virtual Screening, Mechanistic Insights, and Structure-Activity Relationship Analyses

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

  • ACS Infect Dis. 2025 Apr 11;11(4):998-1007. doi: 10.1021/acsinfecdis.4c01045.
Pietro Sciò 1,  Viola Camilla Scoffone 2,  Anastasia Parisi 1,  Marianna Bufano 1,  Martina Caneva 2,  Gabriele Trespidi 2,  Samuele Irudal 2,  Giulia Barbieri 2,  Lisa Cariani 3,  Beatrice Silvia Orena 3,  Valeria Daccò 4,  Francesco Imperi 5,  Silvia Buroni 2,  Antonio Coluccia 1
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome 00185, Italy.
  • 2 Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia 27100, Italy.
  • 3 SC Microbiology and Virology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
  • 4 Pediatric Department, Cystic Fibrosis Pediatric Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
  • 5 Department of Science, University of Roma Tre, Rome 00154, Italy.
PMID: 40100965 DOI: 10.1021/acsinfecdis.4c01045
Abstract

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 C11 endowed with an excellent minimum inhibitory concentration value of 2 μg/mL against Staphylococcus aureus. Biochemical assays clarified that compound C11 targets FtsZ by inhibiting its polymerization process. C11 also showed notable antimicrobial activity against S. aureus cystic fibrosis isolates and methicillin-resistant S. aureus strains. Derivative C11 did not show cytotoxicity, while it had a synergistic effect with methicillin. C11 also showed increased survival in the Galleria mellonella Infection model. Lastly, structure-activity relationship and binding mode analyses were reported.

Keywords

FtsZ; antibiotics; antimicrobial resistance; drug discovery; virtual screening.

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