Structural Flexibility of an Inhibitor Overcomes Drug
Resistance Mutations in Staphylococcus aureus FtsZ
Posted on 2017-06-16 - 19:44
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 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.
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Fujita, Junso; Maeda, Yoko; Mizohata, Eiichi; Inoue, Tsuyoshi; Kaul, Malvika; Parhi, Ajit K.; et al. (2017). Structural Flexibility of an Inhibitor Overcomes Drug
Resistance Mutations in Staphylococcus aureus FtsZ. ACS Publications. Collection. https://doi.org/10.1021/acschembio.7b00323
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AUTHORS (9)
JF
Junso Fujita
YM
Yoko Maeda
EM
Eiichi Mizohata
TI
Tsuyoshi Inoue
MK
Malvika Kaul
AP
Ajit K. Parhi
EL
Edmond J. LaVoie
DP
Daniel S. Pilch
HM
Hiroyoshi Matsumura