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 that express either G196S or G193D mutant FtsZ. We present the crystal structures of TXA6101 in complex with both wildtype SaFtsZ and G196S mutant SaFtsZ, as well the crystal structure of TXA707 in complex with wildtype 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 clash 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 the 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 a reduced susceptibility to mutational resistance.
a b s t r a c tThe bacterial cell-division protein FtsA anchors FtsZ to the cytoplasmic membrane. But how FtsA and FtsZ interact during membrane division remains obscure. We have solved 2.2 Å resolution crystal structure for FtsA from Staphylococcus aureus. In the crystals, SaFtsA molecules within the dimer units are twisted, in contrast to the straight filament of FtsA from Thermotoga maritima, and the half of S12-S13 hairpin regions are disordered. We confirmed that SaFtsZ and SaFtsA associate in vitro, and found that SaFtsZ GTPase activity is enhanced by interaction with SaFtsA.
Structured summary of protein interactions:SaFtsA and SaFtsZ bind by comigration in non denaturing gel electrophoresis (View interaction) SaFtsZ and SaFtsA bind by molecular sieving (View interaction) SaFtsA and SaFtsA bind by x-ray crystallography (View interaction)
The new oral penem antibiotic SUN5555 shows broad antibacterial activity against both aerobic and anaerobic Gram-positive and Gram-negative bacteria. SUN5555is highly stable against various /3-lactamases. It binds preferentially to the penicillin-binding proteins 2 and 1A of Escherichia coli.
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