Parallel solid synthesis of inhibitors of the essential cell division FtsZ enzyme as a new potential class of antibacterials.
As a model system for designing new inhibitors of bacterial cell division, we studied the essential and highly conserved FtsZ GTPase from Pseudomonas aeruginosa. A collection of GTP analogues were prepared using the solid-phase parallel synthesis approach. The synthesized GTP analogues inhibited the GTPase activity of FtsZ with IC(50) values between 450microM and 2.6mM, and 5 compounds inhibited Staphylococcus aureus growth in a biological assay. The FtsZ spectrophotometric assay developed for screening of synthesized compounds is the first step in identification of antibacterials targeting the bacterial cell division essential proteins.
Paradis-Bleau
Catherine
C
CREFSIP, Département de Biologie Médicale, Faculté de médecine, Université Laval, Sainte-Foy, Que., Canada G1K 7P4.
Beaumont
Mélanie
M
Sanschagrin
François
F
Voyer
Normand
N
Levesque
Roger C
RC
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; C071525:FtsZ protein, Bacteria; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases