Inhibitors of Bacterial Cell Partitioning

Jindal, Bhavya; Bhattacharya, Anusri; Panda, Dulal

doi:10.1002/9783527659685.ch7

Cited by 4 publications

(8 citation statements)

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“…Filamentous temperature-sensitive mutant Z (FtsZ), the prokaryotic counterpart of tubulin, drives the cell division process in bacteria; , its assembly and disassembly mechanism regulates the formation and functioning of the dynamic Z-ring at the midcell position, the prerequisite for efficient cell division in bacteria. The disruption of Z-ring formation by external agents has been found to have a lethal effect on cell growth. , In addition, the perturbation of FtsZ assembly induces filamentation in bacterial cells, leading to cell death. Several studies have identified small molecule inhibitors that directly target FtsZ assembly in cells and, in turn, arrest bacterial proliferation. − In addition, the broad conservation of FtsZ among prokaryotes and its constant intracellular concentration make it an attractive target for antibacterial drug discovery programs. − …”

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confidence: 99%

“…The disruption of Z-ring formation by external agents has been found to have a lethal effect on cell growth. , In addition, the perturbation of FtsZ assembly induces filamentation in bacterial cells, leading to cell death. Several studies have identified small molecule inhibitors that directly target FtsZ assembly in cells and, in turn, arrest bacterial proliferation. − In addition, the broad conservation of FtsZ among prokaryotes and its constant intracellular concentration make it an attractive target for antibacterial drug discovery programs. − …”

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A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ

et al. 2017

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Inhibition of FtsZ assembly has been found to stall bacterial cell division. Here, we report the identification of a potent carbocyclic curcumin analogue (2d) that inhibits Bacillus subtilis 168 cell proliferation by targeting the assembly of FtsZ. 2d also showed potent inhibitory activity (minimum inhibitory concentrations of 2-4 mg/L) against several clinically important species of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In addition, 2d displayed a significantly reduced inhibitory effect on human cervical cancer cells in comparison to its effect on bacterial cells. Using live cell imaging of GFP-FtsZ by confocal microscopy, 2d was found to rapidly perturb the cytokinetic FtsZ rings in Bacillus subtilis cells. The immunofluorescence imaging of FtsZ also showed that 2d destroyed the Z-ring in bacteria within 5 min. Prolonged treatment with 2d produced filamentous bacteria, but 2d had no detectable effect either on the nucleoids or on the membrane potential of bacteria. 2d inhibited FtsZ assembly in vitro, whereas it had minimal effects on tubulin assembly. Interestingly, 2d strongly enhanced the GTPase activity of FtsZ and reduced the GTPase activity of tubulin. Furthermore, 2d bound to purified FtsZ with a dissociation constant of 4.0 ± 1.1 μM, and the binding of 2d altered the secondary structures of FtsZ. The results together suggested that the non-natural curcumin analogue 2d possesses powerful antibacterial activity against important pathogenic bacteria, and the evidence indicates that 2d inhibits bacterial proliferation by targeting FtsZ.

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A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ

et al. 2017

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“… 1 , 2 Recent studies have recognized FtsZ as a promising antimicrobial drug target. 3 − 8 Several inhibitors of FtsZ that inhibit the proliferation of Gram-positive and Gram-negative bacteria by affecting FtsZ assembly dynamics have been identified. 7 − 18 Because FtsZ is strongly homologous to tubulin in structure but weakly similar to tubulin in sequence, small molecule inhibitors of FtsZ may also show activities against mammalian cells.…”

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SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly

et al. 2014

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FtsZ has been recognized as a promising antimicrobial drug target because of its vital role in bacterial cell division. In this work, we found that a taxane SB-RA-2001 inhibited the proliferation of Bacillus subtilis 168 and Mycobacterium smegmatis cells with minimal inhibitory concentrations of 38 and 60 μM, respectively. Cell lengths of these microorganisms increased remarkably in the presence of SB-RA-2001, indicating that it inhibits bacterial cytokinesis. SB-RA-2001 perturbed the formation of the FtsZ ring in B. subtilis 168 cells and also affected the localization of the late cell division protein, DivIVA, at the midcell position. Flow cytometric analysis of the SB-RA-2001-treated cells indicated that the compound did not affect the duplication of DNA in B. subtilis 168 cells. Further, SB-RA-2001 treatment did not affect the localization of the chromosomal partitioning protein, Spo0J, along the two ends of the nucleoids and also had no discernible effect on the nucleoid segregation in B. subtilis 168 cells. The agent also did not appear to perturb the membrane potential of B. subtilis 168 cells. In vitro, SB-RA-2001 bound to FtsZ with modest affinity, promoted the assembly and bundling of FtsZ protofilaments, and reduced the GTPase activity of FtsZ. GTP did not inhibit the binding of SB-RA-2001 to FtsZ, suggesting that it does not bind to the GTP binding site on FtsZ. A computational analysis indicated that SB-RA-2001 binds to FtsZ in the cleft region between the C-terminal domain and helix H7, and the binding site of SB-RA-2001 on FtsZ resembled that of PC190723, a well-characterized inhibitor of FtsZ. The findings collectively suggested that SB-RA-2001 inhibits bacterial proliferation by targeting the assembly dynamics of FtsZ, and this can be exploited further to develop potent FtsZ-targeted antimicrobials.

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“…Inhibition of the formation of the divisome complex has been found to stall bacterial division [3]. Recent studies have identified FtsZ, a highly conserved protein, as a potential antibacterial target [4][5][6][7][8][9][10][11]. Some of the FtsZ-targeted antibacterial agents such as PC190723 [12][13][14], zantrin Z3 [15] and OTBA [16] were found to enhance FtsZ assembly in vitro while zantrins Z1, Z2 and Z4 [15], CCR-11 [17], PC58538 and PC170942 were found to inhibit the assembly of FtsZ in vitro [18].…”

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“…Some of the FtsZ‐targeted antibacterial agents such as PC190723 , zantrin Z3 and OTBA were found to enhance FtsZ assembly in vitro while zantrins Z1, Z2 and Z4 , CCR‐11 , PC58538 and PC170942 were found to inhibit the assembly of FtsZ in vitro . Several small molecule inhibitors of FtsZ have been found to increase the length of bacterial cells and to inhibit bacterial cell division .…”

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

et al. 2015

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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 μm 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.

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Inhibitors of Bacterial Cell Partitioning

Cited by 4 publications

References 154 publications

A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ

A Carbocyclic Curcumin Inhibits Proliferation of Gram-Positive Bacteria by Targeting FtsZ

SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly

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

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