Sciò Pietro, Scoffone Viola Camilla, Parisi Anastasia, Bufano Marianna, Caneva Martina, Trespidi Gabriele, Irudal Samuele, Barbieri Giulia, Cariani Lisa, Orena Beatrice Silvia, Daccò Valeria, Imperi Francesco, Buroni Silvia, Coluccia Antonio
Department of Drug Chemistry and Technologies Laboratory Affiliated with the Institute Pasteur Italy - Cenci Bolognetti Foundation, Sapienza University of Rome, Rome 00185, Italy.
Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia 27100, Italy.
ACS Infect Dis. 2025 Apr 11;11(4):998-1007. doi: 10.1021/acsinfecdis.4c01045. Epub 2025 Mar 18.
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 endowed with an excellent minimum inhibitory concentration value of 2 μg/mL against Staphylococcus aureus. Biochemical assays clarified that compound targets FtsZ by inhibiting its polymerization process. also showed notable antimicrobial activity against cystic fibrosis isolates and methicillin-resistant strains. Derivative did not show cytotoxicity, while it had a synergistic effect with methicillin. also showed increased survival in the Galleria mellonella infection model. Lastly, structure-activity relationship and binding mode analyses were reported.
抗菌药物耐药性（AMR）对全球人类健康构成重大威胁。2019年约有500万人死亡归因于AMR，预计这一数字还会恶化，到2050年将达到1000万人死亡。在寻找能够应对AMR的新化合物过程中，FtsZ抑制剂是一个有价值的选择。在本研究中，报告了一种基于结构的虚拟筛选方法，该方法鉴定出一种衍生物，其对金黄色葡萄球菌的最低抑菌浓度值为2μg/mL，表现优异。生化分析表明，该化合物通过抑制FtsZ的聚合过程来靶向FtsZ。它对囊性纤维化分离株和耐甲氧西林菌株也表现出显著的抗菌活性。衍生物未表现出细胞毒性，同时它与甲氧西林具有协同作用。在大蜡螟感染模型中它还显示出存活率提高。最后，报告了构效关系和结合模式分析。
