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BT-benzo-29 inhibits bacterial cell proliferation by perturbing FtsZ assembly

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Title BT-benzo-29 inhibits bacterial cell proliferation by perturbing FtsZ assembly
 
Creator RAY, S
JINDAL, B
KUNAL, K
SUROLIA, A
PANDA, D
 
Subject SMALL-MOLECULE INHIBITORS
DIVISION PROTEIN FTSZ
BACILLUS-SUBTILIS
MYCOBACTERIUM-TUBERCULOSIS
ESCHERICHIA-COLI
TARGETING FTSZ
CYTOKINESIS
MEMBRANE
AGENTS
BINDING
bacterial cell division
cytokinesis
fluorescence
membrane integrity
membrane potential
 
Description We have identified a potent antibacterial agent N-(4-sec-butylphenyl)-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4-carboxamide (BT-benzo-29) from a library of benzimidazole derivatives that stalled bacterial division by inhibiting FtsZ assembly. A short (5 min) exposure of BT-benzo-29 disassembled the cytokinetic Z-ring in Bacillus subtilis cells without affecting the cell length and nucleoids. BT-benzo-29 also perturbed the localization of early and late division proteins such as FtsA, ZapA and SepF at the mid-cell. Further, BT-benzo-29 bound to FtsZ with a dissociation constant of 24 +/- 3 m and inhibited the assembly and GTPase activity of purified FtsZ. A docking analysis suggested that BT-benzo-29 may bind to FtsZ at the C-terminal domain near the T7 loop. BT-benzo-29 displayed significantly weaker inhibitory effects on the assembly and GTPase activity of two mutants (L272A and V275A) of FtsZ supporting the prediction of the docking analysis. Further, BT-benzo-29 did not appear to inhibit DNA duplication and nucleoid segregation and it did not perturb the membrane potential of B. subtilis cells. The results suggested that BT-benzo-29 exerts its potent antibacterial activity by inhibiting FtsZ assembly. Interestingly, BT-benzo-29 did not affect the membrane integrity of mammalian red blood cells. BT-benzo-29 bound to tubulin with a much weaker affinity than FtsZ and exerted significantly weaker effects on mammalian cells than on the bacterial cells indicating that the compound may have a strong antibacterial potential.
 
Publisher WILEY-BLACKWELL
 
Date 2016-01-15T09:37:09Z
2016-01-15T09:37:09Z
2015
 
Type Article
 
Identifier FEBS JOURNAL, 282(20)4015-4033
1742-464X
1742-4658
http://dx.doi.org/10.1111/febs.13403
http://dspace.library.iitb.ac.in/jspui/handle/100/18269
 
Language en