LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens

ABSTRACT The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discove...

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Autores principales:	Andrew P. Tomaras, Craig J. McPherson, Michael Kuhn, Arlene Carifa, Lisa Mullins, David George, Charlene Desbonnet, Tess M. Eidem, Justin I. Montgomery, Matthew F. Brown, Usa Reilly, Alita A. Miller, John P. O’Donnell
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e21fa61d149c45b28c2a269c230984e1
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spelling	oai:doaj.org-article:e21fa61d149c45b28c2a269c230984e12021-11-15T15:45:54ZLpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens10.1128/mBio.01551-142150-7511https://doaj.org/article/e21fa61d149c45b28c2a269c230984e12014-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01551-14https://doaj.org/toc/2150-7511ABSTRACT The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor. IMPORTANCE New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.Andrew P. TomarasCraig J. McPhersonMichael KuhnArlene CarifaLisa MullinsDavid GeorgeCharlene DesbonnetTess M. EidemJustin I. MontgomeryMatthew F. BrownUsa ReillyAlita A. MillerJohn P. O’DonnellAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 5 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Andrew P. Tomaras Craig J. McPherson Michael Kuhn Arlene Carifa Lisa Mullins David George Charlene Desbonnet Tess M. Eidem Justin I. Montgomery Matthew F. Brown Usa Reilly Alita A. Miller John P. O’Donnell LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
description	ABSTRACT The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited to avoid many of the preexisting antibiotic resistance mechanisms that are rapidly disseminating to new strains. The discovery of small-molecule inhibitors of LpxC, the enzyme responsible for the first committed step in the biosynthesis of lipid A, represents a clinically unprecedented strategy to specifically act against Gram-negative organisms such as Pseudomonas aeruginosa and members of the Enterobacteriaceae. In this report, we describe the microbiological characterization of LpxC-4, a recently disclosed inhibitor of this bacterial target, and demonstrate that its spectrum of activity extends to several of the pathogenic species that are most threatening to human health today. We also show that spontaneous generation of LpxC-4 resistance occurs at frequencies comparable to those seen with marketed antibiotics, and we provide an in-depth analysis of the mechanisms of resistance utilized by target pathogens. Interestingly, these isolates also served as tools to further our understanding of the regulation of lipid A biosynthesis and enabled the discovery that this process occurs very distinctly between P. aeruginosa and members of the Enterobacteriaceae. Finally, we demonstrate that LpxC-4 is efficacious in vivo against multiple strains in different models of bacterial infection and that the major first-step resistance mechanisms employed by the intended target organisms can still be effectively treated with this new inhibitor. IMPORTANCE New antibiotics are needed for the effective treatment of serious infections caused by Gram-negative pathogens, and the responsibility of identifying new drug candidates rests squarely on the shoulders of the infectious disease community. The limited number of validated cellular targets and approaches, along with the increasing amount of antibiotic resistance that is spreading throughout the clinical environment, has prompted us to explore the utility of inhibitors of novel targets and pathways in these resistant organisms, since preexisting target-based resistance should be negligible. Lipid A biosynthesis is an essential process for the formation of lipopolysaccharide, which is a critical component of the Gram-negative outer membrane. In this report, we describe the in vitro and in vivo characterization of novel inhibitors of LpxC, an enzyme whose activity is required for proper lipid A biosynthesis, and demonstrate that our lead compound has the requisite attributes to warrant further consideration as a novel antibiotic.
format	article
author	Andrew P. Tomaras Craig J. McPherson Michael Kuhn Arlene Carifa Lisa Mullins David George Charlene Desbonnet Tess M. Eidem Justin I. Montgomery Matthew F. Brown Usa Reilly Alita A. Miller John P. O’Donnell
author_facet	Andrew P. Tomaras Craig J. McPherson Michael Kuhn Arlene Carifa Lisa Mullins David George Charlene Desbonnet Tess M. Eidem Justin I. Montgomery Matthew F. Brown Usa Reilly Alita A. Miller John P. O’Donnell
author_sort	Andrew P. Tomaras
title	LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
title_short	LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
title_full	LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
title_fullStr	LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
title_full_unstemmed	LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens
title_sort	lpxc inhibitors as new antibacterial agents and tools for studying regulation of lipid a biosynthesis in gram-negative pathogens
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/e21fa61d149c45b28c2a269c230984e1
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LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens

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