A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Chia I. Liu, George Y. Liu, Yongcheng Song, Fenglin Yin, Mary E. Hensler, Wen-Yih Jeng, Victor Nizet, Andrew H.J. Wang, Eric Oldfield

Research output: Contribution to journalArticle

264 Citations (Scopus)

Abstract

Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ∼100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.

Original languageEnglish
Pages (from-to)1391-1394
Number of pages4
JournalScience
Volume319
Issue number5868
DOIs
Publication statusPublished - 2008 Mar 7

Fingerprint

Anticholesteremic Agents
Virulence
Staphylococcus aureus
Farnesyl-Diphosphate Farnesyltransferase
Cholesterol
Community-Acquired Infections
Virulence Factors
Carotenoids
Methicillin-Resistant Staphylococcus aureus
Human Activities
Reactive Oxygen Species
Neutrophils
Public Health
Bacteria
Infection
staphyloxanthin

All Science Journal Classification (ASJC) codes

  • General

Cite this

Liu, C. I., Liu, G. Y., Song, Y., Yin, F., Hensler, M. E., Jeng, W-Y., ... Oldfield, E. (2008). A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science, 319(5868), 1391-1394. https://doi.org/10.1126/science.1153018
Liu, Chia I. ; Liu, George Y. ; Song, Yongcheng ; Yin, Fenglin ; Hensler, Mary E. ; Jeng, Wen-Yih ; Nizet, Victor ; Wang, Andrew H.J. ; Oldfield, Eric. / A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. In: Science. 2008 ; Vol. 319, No. 5868. pp. 1391-1394.
@article{d98c1d1474a5484685803563ffc77183,
title = "A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence",
abstract = "Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ∼100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.",
author = "Liu, {Chia I.} and Liu, {George Y.} and Yongcheng Song and Fenglin Yin and Hensler, {Mary E.} and Wen-Yih Jeng and Victor Nizet and Wang, {Andrew H.J.} and Eric Oldfield",
year = "2008",
month = "3",
day = "7",
doi = "10.1126/science.1153018",
language = "English",
volume = "319",
pages = "1391--1394",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "5868",

}

Liu, CI, Liu, GY, Song, Y, Yin, F, Hensler, ME, Jeng, W-Y, Nizet, V, Wang, AHJ & Oldfield, E 2008, 'A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence', Science, vol. 319, no. 5868, pp. 1391-1394. https://doi.org/10.1126/science.1153018

A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. / Liu, Chia I.; Liu, George Y.; Song, Yongcheng; Yin, Fenglin; Hensler, Mary E.; Jeng, Wen-Yih; Nizet, Victor; Wang, Andrew H.J.; Oldfield, Eric.

In: Science, Vol. 319, No. 5868, 07.03.2008, p. 1391-1394.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

AU - Liu, Chia I.

AU - Liu, George Y.

AU - Song, Yongcheng

AU - Yin, Fenglin

AU - Hensler, Mary E.

AU - Jeng, Wen-Yih

AU - Nizet, Victor

AU - Wang, Andrew H.J.

AU - Oldfield, Eric

PY - 2008/3/7

Y1 - 2008/3/7

N2 - Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ∼100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.

AB - Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration ∼100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.

UR - http://www.scopus.com/inward/record.url?scp=40449088993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40449088993&partnerID=8YFLogxK

U2 - 10.1126/science.1153018

DO - 10.1126/science.1153018

M3 - Article

C2 - 18276850

AN - SCOPUS:40449088993

VL - 319

SP - 1391

EP - 1394

JO - Science

JF - Science

SN - 0036-8075

IS - 5868

ER -