A benzamide-dependent ftsZ mutant reveals residues crucial for Z-ring assembly

Mol Microbiol. 2016 Mar;99(6):1028-42. doi: 10.1111/mmi.13286. Epub 2015 Dec 22.


In almost all bacteria, cell division is co-ordinated by the essential tubulin homologue FtsZ and represents an attractive but as yet unexploited target for new antibiotics. The benzamides, e.g. PC190723, are potent FtsZ inhibitors that have the potential to yield an important new class of antibiotic. However, the evolution of resistance poses a challenge to their development. Here we show that a collection of PC190723-resistant and -dependent strains of Staphylococcus aureus exhibit severe growth and morphological defects, questioning whether these ftsZ mutations would be clinically relevant. Importantly, we show that the most commonly isolated substitution remains sensitive to the simplest benzamide 3-MBA and likely works by occluding compound binding. Extending this analysis to Bacillus subtilis, we isolated a novel benzamide-dependent strain that divides using unusual helical division events. The ftsZ mutation responsible encodes the substitution of a highly conserved residue, which lies outside the benzamide-binding site and forms part of an interface between the N- and C-terminal domains that we show is necessary for normal FtsZ function. Together with an intragenic suppressor mutation that mimics benzamide binding, the results provide genetic evidence that benzamides restrict conformational changes in FtsZ and also highlights their utility as tools to probe bacterial division.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Bacillus subtilis / drug effects
  • Bacillus subtilis / metabolism
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Benzamides / pharmacology*
  • Binding Sites
  • Cell Division / drug effects
  • Cytoskeletal Proteins / antagonists & inhibitors*
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • Drug Resistance, Bacterial
  • Mutagenesis, Site-Directed
  • Mutation
  • Pyridines / pharmacology*
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / metabolism
  • Thiazoles / pharmacology*


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Benzamides
  • Cytoskeletal Proteins
  • FtsZ protein, Bacteria
  • PC190723
  • Pyridines
  • Thiazoles