Targeting FtsZ Activity Using Novel Antibacterials: Screening Assays, Small Molecule Hits, and Synthetic Pathways to Potent Natural Products

Summary Inhibition of bacterial septation machinery represents a promising approach for countering antibiotic-resistant bacteria. One such approach targets FtsZ, an essential protein and key mediator of bacterial cell division, which is highly conserved in prokaryotes, yet absent in the mitochondria of higher eukaryotes. Since FtsZ consumes GTP during the cytokinetic FtsZ ring (Z-ring) assembly, much like its eukaryotic analog tubulin during microtubule dynamics in mitosis, it is susceptible to inactivation by compounds that interfere with its assembly-dependent GTPase activity. These compounds present striking parallels to microtubule-targeting anti-mitotic drugs, whereby FtsZ inhibitors either hyperstabilize or destabilize FtsZ filaments, much like how Taxol and vinblastine hyperstabilize or destabilize microtubules in cancer cells, respectively.

Early efforts to target FtsZ have been hindered by few high affinity hits and a general lack of mechanistic understanding of how small molecules perturbed FtsZ assembly in vitro and in vivo. Here, new biochemical and whole cell screens developed by RayChaudhuri and Kirschner have uncovered an unprecedented number of small molecules inhibiting FtsZ, as well as potentially other essential bacterial septation proteins. This rich harvest of inhibitors suggests promising opportunities to expand screening with new chemical libraries.

Applications Commercial Applications and Markets Compounds targeting FtsZ may be developed as broad spectrum antibacterials, relevant to both gram positive and gram negative bacteria. Increasing numbers of drug-resistant infections, including MRSA and a shortage of pipeline development by pharmaceuticals have created significant opportunities for novel antibacterials. The CDC estimates that 2 million individuals will acquire a hospital bacterial infection annually, with 90,000 of these cases resulting in death. Overall, the total market for antibacterials is valued at approximately $25B, with the hospital anti-bacterial market representing $8B. For Further Information Please Contact the Director of Business Development Michal Preminger Email: michal_preminger@hms.harvard.edu Telephone: (617) 432-0920

Inventor(s): Kirschner, Marc W

Type of Offer: Licensing



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