FtsZ blocker developed at Merck

Researchers at Merck Research Laboratories have discovered a small-molecule drug that blocks the activity of FtsZ, an emerging therapeutic target for antibacterial agents. The emergence of bacterial resistance to antibiotics is a major health problem and it is critical to develop new antibiotics with novel modes of action.

FtsZ is a tubulin-like GTPase, and is thought to play an essential role in bacterial cell division, with homologous versions of the enzyme present in almost all bacteria. However, despite its similar activity to tubulin, its structure differs sufficiently to suggest that inhibitors could be designed without activity on human homologues.

During cell division, FtsZ forms polymers in the presence of GTP, which recruit other division proteins to make the cell division apparatus. A septum, built using the protein, assembles at the centre of the cell, and this molecular 'purse string' is linked to the inner surface of the plasma membrane. As it contracts, it pulls the membrane together and separates the two cells.

Inhibition of FtsZ polymerisation should prevent cells from dividing, leading to cell death, according to the researchers.

Using a fluorescent FtsZ polymerisation assay, the Merck researchers screened over 100,000 extracts of microbial fermentation broths and plants. Subsequent fractionation led to the identification of a viriditoxin which blocked FtsZ polymerisation and inhibited GTPase activity.

The viriditoxin exhibited broad-spectrum antibacterial activity against clinically-relevant Gram positive pathogens, including methicillin-resistant Staphylococcus aureus​ and vancomycin-resistant Enterococci, without affecting viability of mammalian cells.

The researchers note that the viriditoxin may not be suitable as a drug candidate itself, but could become a useful tool for drug discovery as well as an important tool for biological studies in the field of cell division.