Identification of a New Class of FtsZ Inhibitors by Structure-Based Design and in Vitro Screening

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• 作者：Fung-Yi Chan ; Ning Sun ; Marco A. C. Neves ; Polo Chun-Hung Lam ; Wai-Hong Chung ; Lai-King Wong ; Ho-Yin Chow ; Dik-Lung Ma ; Pak-Ho Chan ; Yun-Chung Leung ; Tak-Hang Chan ; Ruben Abagyan ; Kwok-Yin Wong
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：August 26, 2013
• 年：2013
• 卷：53
• 期：8
• 页码：2131-2140
• 全文大小：468K
• 年卷期：v.53,no.8(August 26, 2013)
• ISSN：1549-960X

文摘

The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure鈥揳ctivity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC₅₀ and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action.