# FtsZ Interactions and Biomolecular Condensates as Potential Targets for New Antibiotics
## 1 Introduction
(**f**) The pole-to-pole oscillatory waves of the MinCDE system on the cytoplasmic membrane prevent FtsZ polymerization at the cell poles. that, together with ZapB and the DNA binding protein MatP, forms a complex involved in Z-ring positioning called the Ter-linkage [22] (Figure 1e). Self-association of FtsZ leads to different types of higher-order structures depending on the conditions (Figure 2). Single-stranded polymers are formed through head-to-tail interactions between globular regions of two subunits [23]. Triggered by GTP binding, polymerization occurs above a critical concentration of protein [24], following a cooperative association mechanism [25]. Active GTPase sites are formed at the contact interface between two monomers [7]. The sizes of the filaments, which remain assembled until GDP accumulates due to GTP hydrolysis, depend on the conditions [26; 27; 28; 29; 30] and they laterally associate into bundles in crowded environments [31; 32; 33]. There is extensive literature available on the polymerization of FtsZ (see, for instance, [25]) and its inhibition, which leads to suppression of cell division and cell death [34]. When bound to GDP, FtsZ forms non-cooperative isodesemic oligomers whose size is modulated by salt and magnesium [35], and which increase in length in physiological crowding conditions [36]. In vivo, this GDP form of FtsZ is likely transient because of rapid exchange with GTP, except during starvation conditions. The GDP form of FtsZ is active in recognition of other proteins, including the aforementioned ZipA, MinC, and SlmA [37; 38; 39]. FtsZ-GDP is also a key player in the sequestration mechanisms used by FtsZ polymerization antagonists like the DNA damage-inducible SulA protein or the Kil peptide expressed by infecting bacteriophage \(\lambda\)[40; 41] (Figure 1c,d). In addition to assembling as polymers, it was recently shown that FtsZ-GDP can also form dynamic phase-separated condensates (defined as membraneless assemblies in which biomolecules concentrate) in vitro under conditions that mimic the crowded cell cytoplasm [42]. Formation of these condensates is facilitated by the interactions between FtsZ and its antagonist SlmA, which itself is bound to DNA. FtsZ can also form these condensates on its own (Figure 2), albeit less efficiently [43]. The assembly of biomolecular condensates arising from phase separation is emerging as a new mechanism for the spatial organization of biomolecules to optimize their function [44]. It provides a new framework to explain biological processes, as well as clues to decipher the mechanisms underlying major human diseases such as neurodegeneration, cancer, and infections, which may feature dysregulation of condensate formation [45]. Although biomolecular condensates  
Figure 2: Overview of the assemblies formed by FtsZ self-association. FtsZ-GDP monomers form oligomers favored by magnesium and low salt. Under crowding conditions, FtsZ-GDP reversibly phase-separates into biomolecular condensates whose number and size depend on FtsZ, KCl, and Mg\({}^{2+}\) concentrations. GTP addition triggers FtsZ polymerization whether the protein is in oligomers or in condensates. Macromolecular crowding favors the lateral association of single stranded filaments to form bundles. were initially described only in eukaryotic cells, recent research shows bacterial proteins can also assemble into these dynamic membraneless compartments in vivo [46; 47]. For example, proteins involved in essential bacterial processes such as chromosome segregation, DNA compaction and repair, mRNA transcription, or mRNA degradation have been shown to form condensates in vitro and in vivo [47]. How might antibacterial compounds antagonize FtsZ? One mechanism would simply be to hinder FtsZ self-association [1; 48; 49]. Indeed, most anti-FtsZ compounds based on rational drug design perturb FtsZ polymerization, by blocking key sites for GTP binding or FtsZ subunit contacts [48].