Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth

Janish Desai, Yang Wang, Ke Wang, Satish R. Malwal, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1–4 μg mL−1levels. They were found to be potent inhibitors of FPPS; cell growth was partially “rescued” by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2–6 μg mL−1) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1–2 μg mL−1.

Original languageEnglish (US)
Pages (from-to)2205-2215
Number of pages11
JournalChemMedChem
DOIs
StatePublished - Jan 1 2016

Keywords

  • Gram-negative pathogens
  • Staphylococcus aureus
  • cell wall biosynthesis
  • drug discovery
  • membrane proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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