Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. Howe...

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Autores principales:	Nadine Lemaître, Xiaofei Liang, Javaria Najeeb, Chul-Jin Lee, Marie Titecat, Emmanuelle Leteurtre, Michel Simonet, Eric J. Toone, Pei Zhou, Florent Sebbane
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	LpxC animal models antimicrobial drug antimicrobial resistance plague Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a7c043578878492fbc79153fc78569f2
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spelling	oai:doaj.org-article:a7c043578878492fbc79153fc78569f22021-11-15T15:51:43ZCurative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC10.1128/mBio.00674-172150-7511https://doaj.org/article/a7c043578878492fbc79153fc78569f22017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00674-17https://doaj.org/toc/2150-7511ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.Nadine LemaîtreXiaofei LiangJavaria NajeebChul-Jin LeeMarie TitecatEmmanuelle LeteurtreMichel SimonetEric J. ToonePei ZhouFlorent SebbaneAmerican Society for MicrobiologyarticleLpxCanimal modelsantimicrobial drugantimicrobial resistanceplagueMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	LpxC animal models antimicrobial drug antimicrobial resistance plague Microbiology QR1-502
spellingShingle	LpxC animal models antimicrobial drug antimicrobial resistance plague Microbiology QR1-502 Nadine Lemaître Xiaofei Liang Javaria Najeeb Chul-Jin Lee Marie Titecat Emmanuelle Leteurtre Michel Simonet Eric J. Toone Pei Zhou Florent Sebbane Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
description	ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.
format	article
author	Nadine Lemaître Xiaofei Liang Javaria Najeeb Chul-Jin Lee Marie Titecat Emmanuelle Leteurtre Michel Simonet Eric J. Toone Pei Zhou Florent Sebbane
author_facet	Nadine Lemaître Xiaofei Liang Javaria Najeeb Chul-Jin Lee Marie Titecat Emmanuelle Leteurtre Michel Simonet Eric J. Toone Pei Zhou Florent Sebbane
author_sort	Nadine Lemaître
title	Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
title_short	Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
title_full	Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
title_fullStr	Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
title_full_unstemmed	Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC
title_sort	curative treatment of severe gram-negative bacterial infections by a new class of antibiotics targeting lpxc
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/a7c043578878492fbc79153fc78569f2
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Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

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