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

被引：5

作者：

Ball, Haley S. ^{[1
,2
]}

Girma, Misgina ^{[1
]}

Zainab, Mosufa ^{[1
]}

Riley, Honoria ^{[1
]}

Behrendt, Christoph T. ^{[3
]}

Lienau, Claudia ^{[3
]}

Konzuch, Sarah ^{[3
]}

Avelar, Leandro A. A. ^{[3
]}

Lungerich, Beate ^{[3
]}

Soojhawon, Iswarduth ^{[2
]}

Noble, Schroeder M. ^{[2
]}

Kurz, Thomas ^{[3
]}

Couch, Robin D. ^{[1
]}

机构：

[1] George Mason Univ, Dept Chem & Biochem, Manassas, VA 20110 USA

[2] Walter Reed Army Inst Res, Bacterial Dis Branch, Wound Infect Dept, Silver Spring, MD 20910 USA

[3] Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Chem, D-40225 Dusseldorf, Germany

来源：

ACS OMEGA | 2020年 / 5卷 / 10期

关键词：

ANTIMALARIAL; RESISTANCE; DISCOVERY; EVOLUTION;

D O I：

10.1021/acsomega.9b04171

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 alpha-phenylsubstituted 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 mu g/mL; a correlation between the IC50 and MIC values was observed.

引用

页码：5170 / 5175

页数：6

共 31 条

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