Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> 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...

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Autores principales:	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 E. W. Hancock, Mark D. Adams, Samuel W. French, Virgil S. Buslon, Brad Spellberg
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/98a27678de9b43609cdeb2a615fb073e
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spelling	oai:doaj.org-article:98a27678de9b43609cdeb2a615fb073e2021-11-15T15:39:12ZInhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis10.1128/mBio.00312-122150-7511https://doaj.org/article/98a27678de9b43609cdeb2a615fb073e2012-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00312-12https://doaj.org/toc/2150-7511ABSTRACT 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 µg/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. IMPORTANCE Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.Lin LinBrandon TanPaul PantapalangkoorTiffany HoBeverlie BaquirAndrew TomarasJustin I. MontgomeryUsa ReillyElsa G. BarbacciKristine HujerRobert A. BonomoLucia FernandezRobert E. W. HancockMark D. AdamsSamuel W. FrenchVirgil S. BuslonBrad SpellbergAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 5 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 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 E. W. Hancock Mark D. Adams Samuel W. French Virgil S. Buslon Brad Spellberg Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
description	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 µg/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. IMPORTANCE Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.
format	article
author	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 E. W. Hancock Mark D. Adams Samuel W. French Virgil S. Buslon Brad Spellberg
author_facet	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 E. W. Hancock Mark D. Adams Samuel W. French Virgil S. Buslon Brad Spellberg
author_sort	Lin Lin
title	Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
title_short	Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
title_full	Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
title_fullStr	Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
title_full_unstemmed	Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis
title_sort	inhibition of lpxc protects mice from resistant <named-content content-type="genus-species">acinetobacter baumannii</named-content> by modulating inflammation and enhancing phagocytosis
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/98a27678de9b43609cdeb2a615fb073e
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Inhibition of LpxC Protects Mice from Resistant <named-content content-type="genus-species">Acinetobacter baumannii</named-content> by Modulating Inflammation and Enhancing Phagocytosis

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