Inhibition of the Yersinia pestis Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis by α‑Phenyl-Substituted Reverse Fosmidomycin Analogues

Fosmidomycin
inhibits IspC (1-deoxy-d-xylulose 5-phosphate
reductoisomerase), the first committed enzyme in the methylerythritol
phosphate (MEP) pathway of isoprenoid biosynthesis. The MEP pathway
of isoprenoid biosynthesis is essential to the causative agent of
the plague, Yersinia pestis, and is
entirely distinct from the corresponding mammalian pathway. To further
drug development, we established structure–activity relationships
of fosmidomycin analogues by assessing a suite of 17 α-phenyl-substituted
reverse derivatives of fosmidomycin against Y. pestis IspC. Several of these compounds showed increased potency over fosmidomycin
with IC50 values in the nanomolar range. Additionally,
we performed antimicrobial susceptibility testing with Y. pestis A1122 (YpA1122). The bacteria
were susceptible to several compounds with minimal inhibitory concentration
(MIC) values ranging from 128 to 512 μg/mL; a correlation between
the IC50 and MIC values was observed.