title: Identification of a new class of FtsZ inhibitors by structure-based design and in vitro screening.
abstract: 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-activity 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.
authors.affiliation: Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, P. R. China.
authors.forename: Fung-Yi
authors.initials: FY
authors.lastname: Chan
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Marco A C
authors.initials: MA
authors.lastname: Neves
authors.forename: Polo Chun-Hung
authors.initials: PC
authors.lastname: Lam
authors.forename: Wai-Hong
authors.initials: WH
authors.lastname: Chung
authors.forename: Lai-King
authors.initials: LK
authors.lastname: Wong
authors.forename: Ho-Yin
authors.initials: HY
authors.lastname: Chow
authors.forename: Dik-Lung
authors.initials: DL
authors.lastname: Ma
authors.forename: Pak-Ho
authors.initials: PH
authors.lastname: Chan
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Leung
authors.forename: Tak-Hang
authors.initials: TH
authors.lastname: Chan
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Kwok-Yin
authors.initials: KY
authors.lastname: Wong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D011743:Pyrimidines / Q000737:chemistry; D011812:Quinuclidines / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011812:Quinuclidines; D014404:Tubulin; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; C030986:pyrimidine