Structural Insights into the Inhibition of Undecaprenyl Pyrophosphate Synthase from Gram-Positive Bacteria

The polyprenyl lipid undecaprenyl
phosphate (C55P) is
the universal carrier lipid for the biosynthesis of bacterial cell
wall polymers. C55P is synthesized in its pyrophosphate
form by undecaprenyl pyrophosphate synthase (UppS), an essential cis-prenyltransferase that is an attractive target for antibiotic
development. We previously identified a compound (MAC-0547630) that
showed promise as a novel class of inhibitor and an ability to potentiate
β-lactam antibiotics. Here, we provide a structural model for
MAC-0547630’s inhibition of UppS and a structural rationale
for its enhanced effect on UppS from Bacillus subtilis versus Staphylococcus aureus. We also describe the synthesis of a MAC-0547630 derivative (JPD447),
show that it too can potentiate β-lactam antibiotics, and provide
a structural rationale for its improved potentiation. Finally, we
present an improved structural model of clomiphene’s inhibition
of UppS. Taken together, our data provide a foundation for structure-guided
drug design of more potent UppS inhibitors in the future.