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

doi:10.1002/cmdc.201600342

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

ChemMedChem. 2016 Oct 19;11(20):2311-2319. doi: 10.1002/cmdc.201600342. Epub 2016 Aug 31.

Authors

Affiliations

¹ Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL, 61801, USA.
² Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL, 61801, USA.
³ Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
⁴ Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, IL, 61801, USA. [email protected].
⁵ Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL, 61801, USA. [email protected].

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.

Keywords: Staphylococcus aureus; benzoic acids; cell-wall biosynthesis; drug discovery; membrane proteins.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacillus subtilis / cytology
Bacillus subtilis / drug effects*
Bacillus subtilis / enzymology
Bacillus subtilis / growth & development
Benzoates / chemical synthesis
Benzoates / chemistry
Benzoates / pharmacology*
Cell Wall / drug effects
Cell Wall / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Organophosphorus Compounds / chemical synthesis
Organophosphorus Compounds / chemistry
Organophosphorus Compounds / pharmacology*
Phosphoric Monoester Hydrolases / antagonists & inhibitors*
Phosphoric Monoester Hydrolases / metabolism
Staphylococcus aureus / cytology
Staphylococcus aureus / drug effects*
Staphylococcus aureus / enzymology
Staphylococcus aureus / growth & development
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Benzoates
Enzyme Inhibitors
Organophosphorus Compounds
phenylphosphonic acid
Alkyl and Aryl Transferases
undecaprenyl pyrophosphate synthetase
Phosphoric Monoester Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding