Abstract
Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.
Highlights
Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome
While this variability pose of a challenge the development of broad-spectrum of tubulin may rule potential toxicity may concerns inhibitorsfortargeting the GTP-binding site, which antimicrobials, the specificity of this and its structural divergence from the corresponding shows a high homology between the twoarea proteins
The benzamide group interacts via hydrogen bonds with specific residues in the T7 loop of FtsZ (e.g., Val207 and Leu209 in S. aureus) which are conserved across different species [11];
Summary
Cell division is primarily coordinated by the multiprotein complex called the divisome. The trigger point of the process is the binding of FtsZ monomers to GTP, resulting in FtsZ polymerization into single-stranded filaments, following a defined ring-like structure: the Z-ring. This stage is regulated and controlled by multiple mechanisms, both positive and negative, since the correct localization of FtsZ polymerization is essential for obtaining appropriate daughter cells. FtsZ results as the main actor of this essential process, due to its peculiar functions: the ability to bind GTP, to polymerize into protofilaments, and to crosslink, coordinating the formation of the Z-ring, the crucial and limiting step of the cell division cycle
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