Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis

Lin Lin, Brandon Tan, Paul Pantapalangkoor, Tiffany Ho, Beverlie Baquir, Andrew Tomaras, Justin I. Montgomery, Usa Reilly, Elsa G. Barbacci, Kristine Hujer, Robert A. Bonomo, Lucia Fernandez, Robert Hancock, Mark D. Adams, Samuel W. French, Virgil S. Buslon, Brad Spellberg

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 pig/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens.

LanguageEnglish
JournalmBio
Volume3
Issue number5
DOIs
Publication statusPublished - 9 Nov 2012

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Lin, Lin ; Tan, Brandon ; Pantapalangkoor, Paul ; Ho, Tiffany ; Baquir, Beverlie ; Tomaras, Andrew ; Montgomery, Justin I. ; Reilly, Usa ; Barbacci, Elsa G. ; Hujer, Kristine ; Bonomo, Robert A. ; Fernandez, Lucia ; Hancock, Robert ; Adams, Mark D. ; French, Samuel W. ; Buslon, Virgil S. ; Spellberg, Brad. / Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. In: mBio. 2012 ; Vol. 3, No. 5.
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title = "Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis",
abstract = "New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100{\%} of wild-type mice versus 0{\%} of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 pig/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens.",
author = "Lin Lin and Brandon Tan and Paul Pantapalangkoor and Tiffany Ho and Beverlie Baquir and Andrew Tomaras and Montgomery, {Justin I.} and Usa Reilly and Barbacci, {Elsa G.} and Kristine Hujer and Bonomo, {Robert A.} and Lucia Fernandez and Robert Hancock and Adams, {Mark D.} and French, {Samuel W.} and Buslon, {Virgil S.} and Brad Spellberg",
year = "2012",
month = "11",
day = "9",
doi = "10.1128/mBio.00312-12",
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Lin, L, Tan, B, Pantapalangkoor, P, Ho, T, Baquir, B, Tomaras, A, Montgomery, JI, Reilly, U, Barbacci, EG, Hujer, K, Bonomo, RA, Fernandez, L, Hancock, R, Adams, MD, French, SW, Buslon, VS & Spellberg, B 2012, 'Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis', mBio, vol. 3, no. 5. https://doi.org/10.1128/mBio.00312-12

Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. / Lin, Lin; Tan, Brandon; Pantapalangkoor, Paul; Ho, Tiffany; Baquir, Beverlie; Tomaras, Andrew; Montgomery, Justin I.; Reilly, Usa; Barbacci, Elsa G.; Hujer, Kristine; Bonomo, Robert A.; Fernandez, Lucia; Hancock, Robert; Adams, Mark D.; French, Samuel W.; Buslon, Virgil S.; Spellberg, Brad.

In: mBio, Vol. 3, No. 5, 09.11.2012.

Research output: Contribution to journalArticle

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AU - Tan, Brandon

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AU - Baquir, Beverlie

AU - Tomaras, Andrew

AU - Montgomery, Justin I.

AU - Reilly, Usa

AU - Barbacci, Elsa G.

AU - Hujer, Kristine

AU - Bonomo, Robert A.

AU - Fernandez, Lucia

AU - Hancock, Robert

AU - Adams, Mark D.

AU - French, Samuel W.

AU - Buslon, Virgil S.

AU - Spellberg, Brad

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