5xdt
Staphylococcus aureus FtsZ 12-316 complexed with TXA707
Structural highlights
FunctionFTSZ_STAAR Essential cell division protein that forms a contractile ring structure (Z ring) at the future cell division site. The regulation of the ring assembly controls the timing and the location of cell division. One of the functions of the FtsZ ring is to recruit other cell division proteins to the septum to produce a new cell wall between the dividing cells. Binds GTP and shows GTPase activity. Publication Abstract from PubMedIn 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 and TXA707. The greater structural flexibility of TXA6101 relative to TXA707 enables TXA6101 to avoid steric clashes with Ser196 and Asp193. Our structures also demonstrate that the binding of TXA6101 induces previously unobserved conformational rearrangements of SaFtsZ residues in the binding pocket. In aggregate, the structures reported in this work reveal key factors for overcoming drug resistance mutations in SaFtsZ and offer a structural basis for the design of FtsZ inhibitors with enhanced antibacterial potency and reduced susceptibility to mutational resistance. Structural Flexibility of an Inhibitor Overcomes Drug Resistance Mutations in Staphylococcus aureus FtsZ.,Fujita J, Maeda Y, Mizohata E, Inoue T, Kaul M, Parhi AK, LaVoie EJ, Pilch DS, Matsumura H ACS Chem Biol. 2017 Jul 21;12(7):1947-1955. doi: 10.1021/acschembio.7b00323. Epub, 2017 Jun 16. PMID:28621933[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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