An inhibitor of FtsZ with potent and selective anti-staphylococcal activity

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi- drug- resistant Staphylococcus aureus. The putative inhibitor- binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol- binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti- staphylococcal therapy.