Structural Flexibility of an Inhibitor Overcomes Drug Resistance Mutations in Staphylococcus aureus FtsZ

In the effort to combat antibiotic resistance, inhibitors of the essential bacterial protein FtsZ have emerged as a promising new class of compounds with clinical potential. One such FtsZ inhibitor (TXA707) is associated with potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to current standard-of-care antibiotics. However, mutations in S. aureus FtsZ (SaFtsZ) that confer resistance to TXA707 have been observed, with mutations in the Gly196 and Gly193 residues being among the most prevalent. Here, we describe structural studies of an FtsZ inhibitor, TXA6101, which retains activity against MRSA isolates that express either G196S or G193D mutant FtsZ. We present the crystal structures of TXA6101 in complex with both wild-type SaFtsZ and G196S mutant SaFtsZ, as well the crystal structure of TXA707 in complex with wild-type SaFtsZ. Comparison of the three structures reveals a molecular basis for the differential targeting abilities of TXA6101 an...