# FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics
## 1 Introduction  
Resistance to antibiotics is already a major health threat and predicted to worsen unless new strategies are discovered to combat bacterial infections. Efforts in this direction include the identification of new potential antibiotic targets. The well characterized bacterial cell division machinery has lately attracted considerable attention in the quest for these new targets, as reflected by the growing number of reports on the subject [1]. This high level of interest is spurred by the general conservation of cell division proteins in most bacterial species, clear differences from proteins involved in cytokinesis of animal cells, and emerging detailed understanding of the regulatory and structural mechanisms underlying the cell division process in several model bacterial systems. Bacterial cell division is orchestrated by the divisome, a dynamic multiprotein complex that coordinates partitioning of daughter chromosomes, localized cell wall synthesis, and membrane invagination in order to achieve robust and reliable separation of daughter cells [2]. Within the divisome, the FtsZ GTPase is considered the central protein of the cytokinesis machinery, as it forms a so-called Z-ring where the other components bind at the division site (Figure 1). Although FtsZ shows high structural similarity with the eukaryotic cytoskeletal protein tubulin, their amino acid sequences are less than 20% identical [3], and there are important differences in their GTP binding sites, polymerization features, and protein partners [4, 5]. Among bacteria and archaea that carry it, FtsZ is largely conserved, with 40-50% sequence identity [6]; FtsZ orthologs are also present in plastidsof algae and plants [1]. Therefore, this protein is a good target for antimicrobials, both for the low probability of cytotoxicity through tubulin cross-inhibition and for potential broad-spectrum activity. FtsZ function relies on its ability to assemble into GTP-dependent polymers and to interact with other divisome proteins. The FtsZ monomer comprises a highly conserved N-terminal globular domain that contains the GTP binding site, an unstructured and variable linker, and a C-terminal domain that includes a short conserved tail [7]. Crucial interactions with other divisome proteins are mediated through the two conserved domains. In _Escherichia coli_, the conserved C-terminal tail binds to negative spatial regulators of FtsZ assembly such as MinC [8; 9; 10] and SImA [11; 12; 13] (Figure 1a,f) as well as the two FtsZ membrane anchors FtsA [14; 15; 16] and ZipA [14; 17; 18; 19] (Figure 1b) and also ClpX, one of the components of the protease complex ClpXP that degrades FtsZ [20; 21] (Figure 1d). FtsZ also interacts with ZapA [20], a protein highly conserved across bacterial species  
Figure 1: Overview of FtsZ hetero-associations in _E. coli_ as possible targets for antibacterials. At the center, representation of a dividing _E. coli_ cell showing the Z-ring assembled at midcell and FtsZ macromolecular interaction systems. (**a**) Scheme of the nucleoid occlusion system mediated by SImA. SImA bound to specific SBS sequences within the bacterial chromosome, except in the Ter macrodomain, inhibits FtsZ polymerization, thus protecting the chromosome from aberrant scission. (**b**) The Z-ring is attached to the inner membrane through the protein anchors ZipA and FtsA. (**c**) Interaction of FtsZ with the bacteriophage \(\lambda\) Kil peptide disrupts FtsZ polymers, resulting in shorter oligomers of variable size. (**d**) SulA protein, induced by the SOS response, transiently inhibits cell division during DNA repair by sequestering FtsZ monomers. ClpXP protease degrades FtsZ, modulating polymer dynamics and Z-ring formation. (**e**) Scheme of the Ter- linkage that contributes to Z-ring positioning at midcell. From the membrane inwards, FtsZ interacts with ZapA, ZapB, and MatP. MatP is bound to _matS_ sequences located in the chromosomal Ter macrodomain.