pc190723 and Bacterial-Infections

Currently, wide-spread antimicrobials resistance among bacterial pathogens continues being a dramatically increasing and serious threat to public health, and thus there is a pressing need to develop new antimicrobials to keep pace with the bacterial resistance. Filamentous temperature-sensitive protein Z (FtsZ), a prokaryotic cytoskeleton protein, plays an important role in bacterial cell division. It as a very new and promising target, garners special attention in the antibacterial research in the recent years. This review describes not only the function and dynamic behaviors of FtsZ, but also the known natural and synthetic inhibitors of FtsZ. In particular, the small molecules recently developed and the future directions of ideal candidates are highlighted.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; Cell Division; Cytoskeletal Proteins

FtsZ is a guanosine triphosphatase (GTPase) that mediates cytokinesis in bacteria. FtsZ is homologous in structure to eukaryotic tubulin and polymerizes in a similar head-to-tail fashion. The study of tubulin's function in eukaryotic cells has benefited greatly from specific and potent small molecule inhibitors, including colchicine and taxol. Although many small molecule inhibitors of FtsZ have been reported, none has emerged as a generally useful probe for modulating bacterial cell division. With the goal of establishing a useful and reliable small molecule inhibitor of FtsZ, a broad biochemical cross-comparison of reported FtsZ inhibitors was undertaken. Several of these molecules, including phenolic natural products, are unselective inhibitors that seem to derive their activity from the formation of microscopic colloids or aggregates. Other compounds, including the natural product viriditoxin and the drug development candidate PC190723, exhibit no inhibition of GTPase activity using protocols in this work or under published conditions. Of the compounds studied, only zantrin Z3 exhibits good levels of inhibition, maintains activity under conditions that disrupt small molecule aggregates, and provides a platform for exploration of structure-activity relationships (SAR). Preliminary SAR studies have identified slight modifications to the two side chains of this structure that modulate the inhibitory activity of zantrin Z3. Collectively, these studies will help focus future investigations toward the establishment of probes for FtsZ that fill the roles of colchicine and taxol in studies of tubulin.

Topics: Anti-Bacterial Agents; Bacillus subtilis; Bacteria; Bacterial Infections; Bacterial Proteins; Cytoskeletal Proteins; Escherichia coli; Humans; Pyridines; Small Molecule Libraries; Staphylococcus aureus; Structure-Activity Relationship; Thiazoles

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; Cytoskeletal Proteins; Drug Design; Drug Resistance, Bacterial; Escherichia coli Proteins; Gene Expression Regulation, Bacterial; Histidine Kinase; Humans; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Sulfonamides; Thiazoles; Virulence; Virulence Factors; Vitamin K 2