Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr)

Christopher M. Armstrong, David J Meyers, Leah S. Imlay, Caren L Meyers, Audrey R. Odom

Research output: Contribution to journalArticle

Abstract

There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs.

Original languageEnglish (US)
Pages (from-to)5511-5519
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number9
DOIs
StatePublished - Sep 1 2015

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Prodrugs
Anti-Infective Agents
Mutation
Genes
Polyisoprenyl Phosphates
Alleles
Escherichia coli
Plasmodium falciparum
fosmidomycin
deoxyxylulose phosphate
Gram-Negative Bacteria
Mycobacterium tuberculosis
Drug Resistance
Libraries
Parasites
Phosphates
Binding Sites
Anti-Bacterial Agents
Cell Line
Enzymes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr). / Armstrong, Christopher M.; Meyers, David J; Imlay, Leah S.; Meyers, Caren L; Odom, Audrey R.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 9, 01.09.2015, p. 5511-5519.

Research output: Contribution to journalArticle

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