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Inhibition of the Yersinia pestis Methylerythritol Phosphate Pathway of Isoprenoid Biosynthesis by α-Phenyl-Substituted Reverse Fosmidomycin Analogues. 2020

Haley S Ball, and Misgina Girma, and Mosufa Zainab, and Honoria Riley, and Christoph T Behrendt, and Claudia Lienau, and Sarah Konzuch, and Leandro A A Avelar, and Beate Lungerich, and Iswarduth Soojhawon, and Schroeder M Noble, and Thomas Kurz, and Robin D Couch
Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States.

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.

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