Bacterial infections are becoming increasingly resistant to available antibiotics, often through a common mechanism of evolution to prevent the binding of drug molecules. While the development of new antibiotics for established targets is one approach to combat these infections, there is a rising need to consider alternate proteins or pathways. The bacterial cell division protein, FtsZ, therefore offers a promising area for therapeutic research. Recently,several reported FtsZ inhibitors that lead to a filamentatous phenotype were demonstrated to act through non-specific interactions. Zantrin Z3 (Z3) was the only molecule to maintain enzymatic activity against B. subtilis FtsZ (BsFtsZ)and E. coli FtsZ (EcFtsZ). In order to elucidate the interactions between FtsZ and Z3, a thorough structure activity relationship (SAR) must be developed. Directed SAR studies, however, are challenging because the binding site is unknown and there is no co-crystal structure of an inhibitor with FtsZ. Furthermore, limited crystal data for BsFtsZ and EcFtsZ makes the development of more potent analogs difficult. We have identified three areas of Z3 where modifications can be made to improve potency and ligand efficiency. Thus far, preliminary work in all three regions has proven insufficient with only minor improvements to solubility and activity. Current efforts are aimed towards cross-couplings to explore a possible hydrophobic cavity in FtsZ. Installing a photo-reactive handle is also under investigation to characterize the cross-linked FtsZ-Z3 complex by mass spectrometry.

Progress towards binding site elucidation of a small molecule inhibitor of FtsZ

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.