Antibiotic resistance
is a major worldwide concern, and new drugs
with mechanistically novel modes of action are urgently needed. Here,
we report the structure-based drug design, synthesis, and evaluation
in vitro and in cellular systems of sialic acid derivatives able to
inhibit the bacterial sialic acid symporter SiaT. We designed and
synthesized 21 sialic acid derivatives and screened their affinity
for SiaT by a thermal shift assay and elucidated the inhibitory mechanism
through binding thermodynamics, computational methods, and inhibitory
kinetic studies. The most potent compounds, which have a 180-fold
higher affinity compared to the natural substrate, were tested in
bacterial growth assays and indicate bacterial growth delay in methicillin-resistant
Staphylococcus aureus
. This study represents the
first example and a promising lead in developing sialic acid uptake
inhibitors as novel antibacterial agents.
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