A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity

Abstract

The prevalence of multidrug resistance among clinically significant bacteria calls for the urgent development of new antibiotics with novel mechanisms of action. In this study, a new small molecule exhibiting excellent inhibition of bacterial cell division with potent antibacterial activity was discovered through cell-based screening. The compound exhibits a broad spectrum of bactericidal activity, including the methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and NDM-1 Escherichia coli. The in vitro and in vivo results suggested that this compound disrupts the dynamic assembly of FtsZ protein and Z-ring formation through stimulating FtsZ polymerization. Moreover, this compound exhibits no activity on mammalian tubulin polymerization and shows low cytotoxicity on mammalian cells. Taken together, these findings could provide a new chemotype for development of antibacterials with FtsZ as the target.

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

“…Interestingly, tiplaxtinin also exhibits potent antibacterial activity against drug-resistant strains such as MRSA and vancomycinresistant E. faecium ATCC 700221. By means of a light scattering assay, the authors determined that this indole derivative enhances FtsZ polymerization in a concentration-dependent manner, a result that is in agreement with that of other FtsZ-targeting compounds already reported [52]. 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].…”

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

“…In addition, it appears to restore the sensitivity of MRSA to methicillin and to be devoid of toxicity on mammalian cells and human erythrocytes. I20 [50] and its p-hydroxy analogue I21 [51] further reduce the activity gap between Gram-positive and Gram-negative strains, with MICs as low as 6 µM on E. coli (including a MDR strain) and 12 µM on MDR P. aeruginosa ( Table 8). The predicted binding mode on S. aureus FtsZ involves docking in the interdomain cleft, with a network of hydrophobic and ionic interactions.…”

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

“…quinolin-1-ium iodide derivative [105,106]. The results revealed that these compounds possess potent antibacterial activity against bacterial strains including MRSA and VRE.…”

“…The results revealed that these compounds possess potent antibacterial activity against bacterial strains including MRSA and VRE. The results of biological study suggested that these compounds disrupt the dynamic assembly of FtsZ protein and Z-ring formation through inhibiting GTPase activity of FtsZ [105,106].…”