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

[Image: see text] 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 con...

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Autores principales: Singh, Dipty, Bhattacharya, Anusri, Rai, Ankit, Dhaked, Hemendra Pal Singh, Awasthi, Divya, Ojima, Iwao, Panda, Dulal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020581/
https://www.ncbi.nlm.nih.gov/pubmed/24749867
http://dx.doi.org/10.1021/bi401356y
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author Singh, Dipty
Bhattacharya, Anusri
Rai, Ankit
Dhaked, Hemendra Pal Singh
Awasthi, Divya
Ojima, Iwao
Panda, Dulal
author_facet Singh, Dipty
Bhattacharya, Anusri
Rai, Ankit
Dhaked, Hemendra Pal Singh
Awasthi, Divya
Ojima, Iwao
Panda, Dulal
author_sort Singh, Dipty
collection PubMed
description [Image: see text] 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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spelling pubmed-40205812015-04-21 SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly Singh, Dipty Bhattacharya, Anusri Rai, Ankit Dhaked, Hemendra Pal Singh Awasthi, Divya Ojima, Iwao Panda, Dulal Biochemistry [Image: see text] 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. American Chemical Society 2014-04-21 2014-05-13 /pmc/articles/PMC4020581/ /pubmed/24749867 http://dx.doi.org/10.1021/bi401356y Text en Copyright © 2014 American Chemical Society
spellingShingle Singh, Dipty
Bhattacharya, Anusri
Rai, Ankit
Dhaked, Hemendra Pal Singh
Awasthi, Divya
Ojima, Iwao
Panda, Dulal
SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title_full SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title_fullStr SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title_full_unstemmed SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title_short SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly
title_sort sb-ra-2001 inhibits bacterial proliferation by targeting ftsz assembly
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020581/
https://www.ncbi.nlm.nih.gov/pubmed/24749867
http://dx.doi.org/10.1021/bi401356y
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