Antibiotic-resistant bacteria are an increasing threat to public health because the rise of resistance has resulted in a dwindling pool of effective antibiotics. New drugs are urgently needed to fight meticillin resistant Staphylococcus aureus (MRSA) and other resistant bacterial pathogens. Publishing in Science, Haydon and colleagues describe a new compound that kills MRSA and other bacteria by targeting the essential cell division protein FtsZ.

...PC190723 is a promising starting point for the future development of anti-staphylococcal drugs...

By screening more than 500 derivatives of 3-methoxybenzamide, a known inhibitor of FtsZ, Haydon et al. identified PC190723, which kills MRSA, together with many species of Staphylococcus and Bacillus subtilis . Streptococcus species, Gram-negative bacteria and eukaryotic cells were unaffected by PC190723. Sequence analyses indicated that bacteria that are not killed by PC190723 have replaced valine 307 in FtsZ with a bulky histidine or arginine residue. This probably prevents the drug from accessing its putative binding site.

Importantly, mice that had been given a lethal intraperitoneal dose of S. aureus were protected by a single injection of PC190723 to the same level as a standard vancomycin treatment. The authors used an in vitro assay to show that PC190723 inhibits the GTPase activity of purified FtsZ. In B. subtilis cells, treatment with PC190723 caused FtsZ, which usually polymerizes to form a ring that encircles the mid-point of the cell, to aggregate into amorphous clumps that were dispersed throughout the cell. Treated B. subtilis failed to divide but continued to grow into long tubules instead of individual rod-shaped cells. PC190723 also inhibited cell division in S. aureus, resulting in the formation of enlarged cells, and ultimately killed the cells. Spontaneous PC190723-resistant S. aureus mutants arose at a rate of 2×10−8; these carried mutations in the ftsZ gene, providing further proof that this drug targets FtsZ.

Despite the potential for resistance to evolve, PC190723 is a promising starting point for the future development of anti-staphylococcal drugs, and the authors propose that it could be useful as part of a combination drug regime.