New application of tiplaxtinin as an effective FtsZ-targeting chemotype for an antimicrobial study

Abstract

The filamenting temperature-sensitive mutant Z (FtsZ) protein is generally recognized as a promising antimicrobial drug target. In the present study, a small organic molecule (tiplaxtinin) was identified for the first time as an excellent cell division inhibitor by using a cell-based screening approach from a library with 250 compounds. Tiplaxtinin possesses potent antibacterial activity against Gram-positive pathogens. Both and results reveal that the compound is able to disrupt dynamic assembly of FtsZ and Z-ring formation effectively through the mechanism of stimulating FtsZ polymerization and impairing GTPase activity.

Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ

“…The on−target activity of I26 on S. aureus FtsZ was thoroughly assessed through light scattering polymerization assays, GTPase assays, and TEM microscopy, revealing concentration−dependent enhancement of polymerization, a decrease in GTPase activity, and a significant increase in protofilament bundling in the presence of the compound. Moreover, I26 induces the mis−localization of GFP−tagged FtsZ in discrete and punctate foci, indicating the mis−formation of the Z−ring [53]. Docking simulations predicted the binding of I26 in the interdomain cleft, supported by hydrophobic interactions in the lipophilic channel and by a set of additional interactions with specific functional groups.…”

“…Antibiotics 2020, 9,69 23 of 28 of GFP−tagged FtsZ in discrete and punctate foci, indicating the mis−formation of the Z−ring [53]. Docking simulations predicted the binding of I26 in the interdomain cleft, supported by hydrophobic interactions in the lipophilic channel and by a set of additional interactions with specific functional groups.…”

Recent Progress in the Development of Small-Molecule FtsZ Inhibitors as Chemical Tools for the Development of Novel Antibiotics

“…Inspired by the preliminary evidence that suggests that NSAIDs (nonsteroidal anti-inflammatory drugs) possess antibacterial properties [68], Mathew and co-workers explored the in vitro anti-tubercular profile and MtbFtsZ activity of a series of compounds based on the scaffold of the NSAID sulindac (59, Figure 12 The indole oxoacetic derivative tiplaxtinin (62, Figure 12) is a human plasminogen activator inhibitor (PAI-1) indicated in the treatment of acute arterial thrombosis [70]. Recently, Sun and coworkers identified its promising profile as an antibacterial against Gram-positive strain and as a potent inhibitor of FtsZ [71]. Firstly, the authors studied the effects of a small library of approximately 250 compounds on B. subtilis morphology, which showed that tiplaxtinin (62) was able to cause the elongation of the rod-shaped microorganism.…”

“…Finally, a The indole oxoacetic derivative tiplaxtinin (62, Figure 12) is a human plasminogen activator inhibitor (PAI-1) indicated in the treatment of acute arterial thrombosis [70]. Recently, Sun and co-workers identified its promising profile as an antibacterial against Gram-positive strain and as a potent inhibitor of FtsZ [71]. Firstly, the authors studied the effects of a small library of approximately 250 compounds on B. subtilis morphology, which showed that tiplaxtinin (62) was able to cause the elongation of the rod-shaped microorganism.…”

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

“…Several characteristics render FtsZ a potential target for the development of new antibacterial agents: (i) it plays an essential role in bacterial cell division [45]; (ii) the structure and function of FtsZ are conserved across bacterial species [17,20]; (iii) it is absent in eukaryotes [69,70]; (iv) its structural and biological properties are well studied. So far, there are no drugs on the market targeting at FtsZ, but many researchers have made great efforts in studying FtsZ targeting compounds and their studies revealed that FtsZ inhibitors can lead to bacterial cell death via inhibition of cell division [71][72][73][74]. Most of these inhibitors will be discussed in the following sections.…”