title: A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ.
abstract: Inhibition of FtsZ assembly has been found to stall bacterial cell division. Here, we report the identification of a potent carbocyclic curcumin analogue (2d) that inhibits Bacillus subtilis 168 cell proliferation by targeting the assembly of FtsZ. 2d also showed potent inhibitory activity (minimum inhibitory concentrations of 2-4 mg/L) against several clinically important species of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In addition, 2d displayed a significantly reduced inhibitory effect on human cervical cancer cells in comparison to its effect on bacterial cells. Using live cell imaging of GFP-FtsZ by confocal microscopy, 2d was found to rapidly perturb the cytokinetic FtsZ rings in Bacillus subtilis cells. The immunofluorescence imaging of FtsZ also showed that 2d destroyed the Z-ring in bacteria within 5 min. Prolonged treatment with 2d produced filamentous bacteria, but 2d had no detectable effect either on the nucleoids or on the membrane potential of bacteria. 2d inhibited FtsZ assembly in vitro, whereas it had minimal effects on tubulin assembly. Interestingly, 2d strongly enhanced the GTPase activity of FtsZ and reduced the GTPase activity of tubulin. Furthermore, 2d bound to purified FtsZ with a dissociation constant of 4.0 ± 1.1 μM, and the binding of 2d altered the secondary structures of FtsZ. The results together suggested that the non-natural curcumin analogue 2d possesses powerful antibacterial activity against important pathogenic bacteria, and the evidence indicates that 2d inhibits bacterial proliferation by targeting FtsZ.
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Paul W
authors.identifier: 0000-0002-4932-2030
authors.initials: PW
authors.lastname: Groundwater
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Narlawar
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Vivian Wan Yu
authors.initials: VW
authors.lastname: Liao
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Anusri
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Kishore
authors.initials: K
authors.lastname: Kunal
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Munikumar
authors.initials: M
authors.lastname: Doddareddy
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Pratik M
authors.initials: PM
authors.lastname: Oza
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Mamidi
authors.affiliation: Microbiology Department, Freeman Hospital , High Heaton, Newcastle upon Tyne NE7 7DN, United Kingdom.
authors.forename: Emma C L
authors.initials: EC
authors.lastname: Marrs
authors.affiliation: Microbiology Department, Freeman Hospital , High Heaton, Newcastle upon Tyne NE7 7DN, United Kingdom.
authors.forename: John D
authors.initials: JD
authors.lastname: Perry
authors.affiliation: Faculty of Pharmacy, The University of Sydney , Pharmacy and Bank Building, Science Road, Sydney, NSW 2006, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076, India.
authors.forename: Dulal
authors.initials: D
authors.lastname: Panda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000648:ultrastructure; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D001665:Binding Sites; D003001:Cloning, Molecular; D003474:Curcumin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D003500:Cyclization; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D006041:Goats; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D057054:Molecular Imaging; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013045:Species Specificity; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D011994:Recombinant Proteins; D014404:Tubulin; D049452:Green Fluorescent Proteins; D003474:Curcumin