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Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ

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Title Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ
 
Creator JAISWAL, R
BEURIA, TK
MOHAN, R
MAHAJAN, SK
PANDA, D
 
Subject cell division protein
mycobacterium-tuberculosis ftsz
microtubule polymerization
antibacterial activity
small-molecule
tubulin
cancer
agents
proliferation
cytoskeleton
 
Description Totarol, a diterpenoid phenol, has been shown to inhibit the proliferation of several pathogenic Gram-positive bacteria including Mycobacterium tuberculosis. In this study, totarol was found to inhibit the proliferation of Bacillus subtilis cells with a minimum inhibitory concentration of 2 mu M. It did not detectably perturb the membrane structure of B. subtilis; it strongly induced the filamentation in B. subtilis cells, suggesting that it inhibits bacterial cytokinesis. Totarol (1.5 mu M) reduced the frequency of the Z-ring occurrence per micrometer of the bacterial cell length but did not affect the nucleoid frequency, suggesting that it blocks cytokinesis by inhibiting the formation of the Z-ring. The assembly dynamics of FtsZ is thought to play an important role in the formation and functioning of the Z-ring, a machine that engineers cytokinesis in bacteria. Since totarol was shown to inhibit the proliferation of M. tuberculosis, we examined the effects of totarol on the assembly dynamics of M. tuberculosis FtsZ (MtbFtsZ) in vitro. Totarol decreased the assembly of MtbFtsZ protofilaments and potently suppressed the GTPase activity of MtbFtsZ. It bound to MtbFtsZ with a dissociation constant of 11 +/- 2.3 mu M. It increased the fluorescence intensity of the MtbFtsZ-1-anilinonaphthalene-8-sulfonic acid complex and inhibited the fluorescence intensity of N-(1-pyrene)maleimide-labeled MtbFtsZ, suggesting that totarol induces conformational changes in MtbFtsZ. The results indicated that totarol can perturb the assembly dynamics of FtsZ protofilaments in the Z-ring. Totarol exhibited extremely weak inhibitory effects on HeLa cell proliferation. It did not affect microtubule organization in HeLa cells. The results suggest that totarol inhibits bacterial proliferation by targeting FtsZ and it may be useful as a lead compound to develop an effective antitubercular drug.
 
Publisher AMER CHEMICAL SOC
 
Date 2011-07-15T03:16:13Z
2011-12-26T12:49:12Z
2011-12-27T05:35:01Z
2011-07-15T03:16:13Z
2011-12-26T12:49:12Z
2011-12-27T05:35:01Z
2007
 
Type Article
 
Identifier BIOCHEMISTRY, 46(14), 4211-4220
0006-2960
http://dx.doi.org/10.1021/bi602573e
http://dspace.library.iitb.ac.in/xmlui/handle/10054/4141
http://hdl.handle.net/10054/4141
 
Language en