Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus

In vitro, in vivo, and crystallographic results

Yongcheng Song, Chia I. Liu, Fu Yang Lin, Hwan No Joo, Mary Hensler, Yi Liang Liu, Wen Yih Jeng, Jennifer Low, George Y. Liu, Victor Nizet, Andrew H J Wang, Eric Oldfield

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for the organism. Here, we report the synthesis and activity of a broad variety of staphyloxanthin biosynthesis inhibitors that inhibit the first committed step in its biosynthesis, condensation of two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by the enzyme dehydrosqualene synthase (CrtM). The most active compounds are phosphonoacetamides that have low nanomolar Ki values for CrtM inhibition and are active in whole bacterial cells and in mice, where they inhibit S. aureus disease progression. We also report the X-ray crystallographic structure of the most active compound, N-3-(3-phenoxyphenyl) propylphosphonoacetamide (IC50 = 8 nM, in cells), bound to CrtM. The structure exhibits a complex network of hydrogen bonds between the polar headgroup and the protein, while the 3-phenoxyphenyl side chain is located in a hydrophobic pocket previously reported to bind farnesyl thiodiphosphate (FsPP), as well as biphenyl phosphonosulfonate inhibitors. Given the good enzymatic, whole cell, and in vivo pharmacologic activities, these results should help guide the further development of novel antivirulence factor-based therapies for S. aureus infections.

Original languageEnglish
Pages (from-to)3869-3880
Number of pages12
JournalJournal of Medicinal Chemistry
Volume52
Issue number13
DOIs
Publication statusPublished - Jul 9 2009
Externally publishedYes

Fingerprint

Virulence Factors
Staphylococcus aureus
Carotenoids
Gold
Inhibitory Concentration 50
Disease Progression
Hydrogen
Color
X-Rays
Enzymes
Infection
staphyloxanthin
In Vitro Techniques
Proteins
dehydrosqualene
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus : In vitro, in vivo, and crystallographic results. / Song, Yongcheng; Liu, Chia I.; Lin, Fu Yang; Joo, Hwan No; Hensler, Mary; Liu, Yi Liang; Jeng, Wen Yih; Low, Jennifer; Liu, George Y.; Nizet, Victor; Wang, Andrew H J; Oldfield, Eric.

In: Journal of Medicinal Chemistry, Vol. 52, No. 13, 09.07.2009, p. 3869-3880.

Research output: Contribution to journalArticle

Song, Y, Liu, CI, Lin, FY, Joo, HN, Hensler, M, Liu, YL, Jeng, WY, Low, J, Liu, GY, Nizet, V, Wang, AHJ & Oldfield, E 2009, 'Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus: In vitro, in vivo, and crystallographic results', Journal of Medicinal Chemistry, vol. 52, no. 13, pp. 3869-3880. https://doi.org/10.1021/jm9001764
Song, Yongcheng ; Liu, Chia I. ; Lin, Fu Yang ; Joo, Hwan No ; Hensler, Mary ; Liu, Yi Liang ; Jeng, Wen Yih ; Low, Jennifer ; Liu, George Y. ; Nizet, Victor ; Wang, Andrew H J ; Oldfield, Eric. / Inhibition of staphyloxanthin virulence factor biosynthesis in Staphylococcus aureus : In vitro, in vivo, and crystallographic results. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 13. pp. 3869-3880.
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