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 IC50 values between 450 μM and 2.6 mM, 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.

GTP analogues were synthesized with a guanine-like moiety linked to an Ala side chain using combinatorial chemistry as FtsZ GTPase inhibitors. Lead compound 14 showed prominent inhibitory and antibacterial activities.Figure optionsDownload as PowerPoint slide