Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase

Yang Wang, Janish Desai, Yonghui Zhang, Satish R. Malwal, Christopher J. Shin, Xinxin Feng, Hong Sun, Guizhi Liu, Rey Ting Guo, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

We synthesized a series of benzoic acids and phenylphosphonic acids and investigated their effects on the growth of Staphylococcus aureus and Bacillus subtilis. One of the most active compounds, 5-fluoro-2-(3-(octyloxy)benzamido)benzoic acid (7, ED50∼0.15 μg mL−1) acted synergistically with seven antibiotics known to target bacterial cell-wall biosynthesis (a fractional inhibitory concentration index (FICI) of ∼0.35, on average) but had indifferent effects in combinations with six non-cell-wall biosynthesis inhibitors (average FICI∼1.45). The most active compounds were found to inhibit two enzymes involved in isoprenoid/bacterial cell-wall biosynthesis: undecaprenyl diphosphate synthase (UPPS) and undecaprenyl diphosphate phosphatase (UPPP), but not farnesyl diphosphate synthase, and there were good correlations between bacterial cell growth inhibition, UPPS inhibition, and UPPP inhibition.

Original languageEnglish (US)
Pages (from-to)2311-2319
Number of pages9
JournalChemMedChem
Volume11
Issue number20
DOIs
StatePublished - 2016

Keywords

  • Staphylococcus aureus
  • benzoic acids
  • 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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