title: Antimicrobial activity of a quinuclidine-based FtsZ inhibitor and its synergistic potential with β-lactam antibiotics.
abstract: Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein that cooperates in the formation of the cytokinetic Z-ring in most bacteria and has thus been recognized as a promising antimicrobial drug target. We have recently used a structure-based virtual screening approach to identify pyrimidine-linked quinuclidines as a novel class of FtsZ inhibitors. In this study, we further investigated the antibacterial properties of one of the most potent compounds (quinuclidine 1) and its synergistic activity with β-lactam antibiotics. Susceptibility results showed that quinuclidine 1 was active against multiple antibiotic-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium with minimal inhibitory concentrations of 24 μg ml(-1). When quinuclidine 1 was combined with β-lactam antibiotics, synergistic antimicrobial activities against antibiotic-resistant strains of S. aureus were found. Further in vitro studies suggest that prevention of FtsZ protofilament formation by quinuclidine 1 impairs the formation of Z-ring, and thus inhibits bacterial division. These findings open a new approach for development of quinuclidine-based FtsZ inhibitors into potent antimicrobial agents.
authors.affiliation: Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Fung-Yi
authors.initials: FY
authors.lastname: Chan
authors.affiliation: Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.affiliation: Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Yun-Chung
authors.initials: YC
authors.lastname: Leung
authors.affiliation: Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Kwok-Yin
authors.initials: KY
authors.lastname: Wong
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D016984:Enterococcus faecium / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects; D047090:beta-Lactams / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011812:Quinuclidines; D047090:beta-Lactams