Design and synthesis of novel FtsZ-targeting antibacterial agents.

摘要

Bacterial infections pose a major health concern worldwide, and the emergence of multi-drug resistant strains of bacteria has intensified the search for new antibiotic treatments with novel mechanisms of action. Bacterial cell division remains a new, currently untargeted pathway making it highly desirable research area for discovering new ways to kill bacteria. FtsZ is a highly conserved, essential bacterial cell division protein that forms the dynamic Z-ring involved in recruitment of other essential proteins and serving as the constricting force for cell division. Inhibiting the function of this key protein disrupts proper cell division, and has therefore become a key target in the search for new antibiotics. There are many known FtsZ inhibitors spanning from natural products such as sanguinarine and berberine, to synthetic derivatives such as GTP analogs and PC190723. The majority of these known inhibitors, however, lack the proper potency, safety profiles, and physiochemical properties required for clinical development. Initial studies involved modifying the structures of two known FtsZ inhibitors, sanguinarine and berberine, to increase potency and explore the structure-activity relationships. Unfortunately, although successfully obtaining analogs with good antibacterial activity, these compounds lacked desired solubility properties for further advancement. This led to the second generation of compounds that lacked a constitutive cationic charge while retaining the antibacterial activity seen with the previous analogs. While these compounds had much better solubility, they possessed a new drawback. Compounds from the second generation were found to be highly protein bound resulting in a significant loss of antibacterial activity when administered in the presence of protein. Studies began to design and synthesize analogs that either exhibited much higher potency or much less protein binding. Although initial attempts at this were unsuccessful, continued efforts are being made to find a FtsZ inhibitor with improved potency, physiochemical properties, and a broader spectrum of antibacterial activity.