FTSZ DIVISIONAL PROTEIN AS THERAPEUTIC TARGET FOR NOVEL ANTIBACTERIAL AGENTS

Jennifer Hsuan-Yu Lin, JHY Lin, M Doddareddy, R Battaje, H Dhaked, S Srivastava, D Panda, DE Hibbs and PW Groundwater

Faculty of Pharmacy, University of Sydney, Sydney, Australia

Abstract

FtsZ is a universal divisional protein in bacteria that is essential for the process of bacterial cytokinesis. FtsZ is conserved across almost all bacterial species; its mammalian homologue, tubulin resembles FtsZ structurally but the two do not share a high degree of sequence similarity. FtsZ is thus considered to be a potential target for the discovery of novel antibacterial agents. Using molecular modelling techniques, a putative binding site was identified; structure-based drug design methods then elicited a series of curcumin analogues as potential candidates. These curcumin analogues were tested and found to inhibit Bacillus subtilis cell proliferation. In addition, a different series of the curcumin analogues were synthesised and tested. Our preliminary findings have demonstrated that two of the curcumin analogues, JL-17 and JL-18, have growth inhibitory activity against Streptococcus pneumoniae, with MIC50s of 541 +/- 30 nM (0.18 - 0.20 mcg/mL) and 939 +/-16 nM (0.31 - 0.32 mcg/mL), respectively. These two compounds were found to be less toxic against eukaryotic cells, such as the L-929 mouse skin cell line, with IC50 of 7 +/- 2.35 mcM and 1.5 +/- 0.4 mcM respectively. More testing will be needed to further elucidate the antibacterial effect for this specific series of curcumin analogues on different strains of bacteria.

Keywords: FtsZ, tubulin, antibacterial, molecular modelling, structure-based drug design, curcumin analogues.