SB-RA-2001 Inhibits Bacterial Proliferation by Targeting
FtsZ Assembly
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Abstract
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 <i>Bacillus subtilis</i> 168 and <i>Mycobacterium smegmatis</i> 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 <i>B. subtilis</i> 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 <i>B. subtilis</i> 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 <i>B. subtilis</i> 168 cells. The agent also did not appear to perturb the membrane
potential of <i>B. subtilis</i> 168 cells. <i>In vitro</i>, 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