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

Haley S Ball; Misgina Girma; Mosufa Zainab; Honoria Riley; Christoph T Behrendt; Claudia Lienau; Sarah Konzuch; Leandro A A Avelar; Beate Lungerich; Iswarduth Soojhawon; Schroeder M Noble; Thomas Kurz; Robin D Couch

doi:10.1021/acsomega.9b04171

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

ACS Omega. 2020 Mar 4;5(10):5170-5175. doi: 10.1021/acsomega.9b04171. eCollection 2020 Mar 17.

Affiliations

¹ Department of Chemistry and Biochemistry, George Mason University, Manassas, Virginia 20110, United States.
² Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
³ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.

Abstract

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.