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Promoting assembly and bundling of FtsZ as a strategy to inhibit bacterial cell division: a new approach for developing novel antibacterial drugs

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Title Promoting assembly and bundling of FtsZ as a strategy to inhibit bacterial cell division: a new approach for developing novel antibacterial drugs
 
Creator BEURIA, TK
SINGH, P
SUROLIA, A
PANDA, D
 
Subject protein ftsz
anticancer drugs
targeting ftsz
small-molecule
tubulin
discovery
protofilaments
antibiotics
agents
cytokinesis
antibacterial agent
bacterial cell division
ftsz polymerization
rhodanine
z-ring
 
Description FtsZ plays an essential role in bacterial cell division. We have used the assembly of FtsZ as a screen to find antibacterial agents with a novel mechanism of action. The effects of 81 compounds of 29 different structural scaffolds on FtsZ assembly in vitro were examined using a sedimentation assay. Out of these 81 compounds, OTBA (3-{5-[4-oxo-2-thioxo-3-(3-trifluoromethylphenyl)-thiazolidin-5-ylidenemethyl]-furan-2-yl}-benzoic acid) was found to promote FtsZ assembly in vitro. OTBA increased the assembly of FtsZ, caused bundling of FtsZ protofilaments, prevented dilution-induced disassembly of FtsZ protofilaments and decreased the GTPase activity in vitro. It bound to FtsZ with an apparent dissociation constant of 15 +/- 1.5 mu M. Furthermore, OTBA inhibited the proliferation of Bacillus subtilis 168 cells with an MIC (minimum inhibitory concentration) of 2 mu M, whereas it exerted minimal effects on mammalian cell proliferation, indicating that it might have a potential use as an antibacterial drug. In the effective proliferation inhibitory concentration range, OTBA induced filamentation in bacteria and also perturbed the formation of the cytokinetic Z-rings in bacteria. However, the agent neither perturbed the membrane structures nor affected the nucleoid segregation in B. subtilis cells. The results suggested that the OTBA inhibited bacterial cytokinesis by perturbing the formation and functioning of the Z-ring via altering FtsZ assembly dynamics. The antibacterial mechanism of action of OTBA is similar to that of the widely used anticancer drug paclitaxel, which inhibits cancer cell proliferation by promoting the assembly of tubulin, a eukaryotic homologue of FtsZ.
 
Publisher PORTLAND PRESS LTD
 
Date 2011-08-27T07:06:45Z
2011-12-26T12:57:47Z
2011-12-27T05:45:16Z
2011-08-27T07:06:45Z
2011-12-26T12:57:47Z
2011-12-27T05:45:16Z
2009
 
Type Article
 
Identifier BIOCHEMICAL JOURNAL, 423(), 61-69
0264-6021
http://dx.doi.org/10.1042/BJ20090817
http://dspace.library.iitb.ac.in/xmlui/handle/10054/11580
http://hdl.handle.net/10054/11580
 
Language en