Berberine Targets Assembly of Escherichia coli Cell Division Protein FtsZ
- 15 February 2008
- journal article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 47 (10), 3225-3234
- https://doi.org/10.1021/bi7018546
Abstract
The ever increasing problem of antibiotic resistance necessitates a search for new drug molecules that would target novel proteins in the prokaryotic system. FtsZ is one such target protein involved in the bacterial cell division machinery. In this study, we have shown that berberine, a natural plant alkaloid, targets Escherichia coli FtsZ, inhibits the assembly kinetics of the Z-ring, and perturbs cytokinesis. It also destabilizes FtsZ protofilaments and inhibits the FtsZ GTPase activity. Saturation transfer difference NMR spectroscopy of the FtsZ−berberine complex revealed that the dimethoxy groups, isoquinoline nucleus, and benzodioxolo ring of berberine are intimately involved in the interaction with FtsZ. Berberine perturbs the Z-ring morphology by disturbing its typical midcell localization and reduces the frequency of Z-rings per unit cell length to half. Berberine binds FtsZ with high affinity (KD ∼ 0.023 µM) and displaces bis-ANS, suggesting that it may bind FtsZ in a hydrophobic pocket. Isothermal titration calorimetry suggests that the FtsZ−berberine interaction occurs spontaneously and is enthalpy/entropy-driven. In silico molecular modeling suggests that the rearrangement of the side chains of the hydrophobic residues in the GTP binding pocket may facilitate the binding of the berberine to FtsZ and lead to inhibition of the association between FtsZ monomers. Together, these results clearly indicate the inhibitory role of berberine on the assembly function of FtsZ, establishing it as a novel FtsZ inhibitor that halts the first stage in bacterial cell division.Keywords
This publication has 49 references indexed in Scilit:
- Inhibition of bacterial cell division protein FtsZ by cinnamaldehydeBiochemical Pharmacology, 2007
- Totarol Inhibits Bacterial Cytokinesis by Perturbing the Assembly Dynamics of FtsZBiochemistry, 2007
- Sanguinarine Blocks Cytokinesis in Bacteria by Inhibiting FtsZ Assembly and BundlingBiochemistry, 2005
- Synthesis of Antimicrobial Natural Products Targeting FtsZ: (±)-Dichamanetin and (±)-2‘ ‘‘-Hydroxy-5‘ ‘-benzylisouvarinol-BOrganic Letters, 2005
- Targeting cell division: Small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethalityProceedings of the National Academy of Sciences of the United States of America, 2004
- Discovery of a Small Molecule That Inhibits Cell Division by Blocking FtsZ, a Novel Therapeutic Target of AntibioticsJournal of Biological Chemistry, 2003
- 2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZJournal of Antimicrobial Chemotherapy, 2002
- Inhibition of Assembly of Bacterial Cell Division Protein FtsZ by the Hydrophobic Dye 5,5′-Bis-(8-anilino-1-naphthalenesulfonate)Journal of Biological Chemistry, 1998
- FtsZ, a prokaryotic homolog of tubulin?Cell, 1995
- FtsZ ring structure associated with division in Escherichia coliNature, 1991