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

Abstract

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 effectivein vitroagainst 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 bacteriumYersinia 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. IMPORTANCEThe rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, wemore » 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 activein vitroagainst 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 byY. pestisand by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.« less

Authors:
; ; ; ; ; ; ; ; ORCiD logo; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1399138
Resource Type:
Journal Article
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Volume: 8; Journal Issue: 4; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Lemaître, Nadine, Liang, Xiaofei, Najeeb, Javaria, Lee, Chul-Jin, Titecat, Marie, Leteurtre, Emmanuelle, Simonet, Michel, Toone, Eric J., Zhou, Pei, Sebbane, Florent, and Nacy, Carol A. Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC. United States: N. p., 2017. Web. doi:10.1128/mBio.00674-17.
Lemaître, Nadine, Liang, Xiaofei, Najeeb, Javaria, Lee, Chul-Jin, Titecat, Marie, Leteurtre, Emmanuelle, Simonet, Michel, Toone, Eric J., Zhou, Pei, Sebbane, Florent, & Nacy, Carol A. Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC. United States. doi:10.1128/mBio.00674-17.
Lemaître, Nadine, Liang, Xiaofei, Najeeb, Javaria, Lee, Chul-Jin, Titecat, Marie, Leteurtre, Emmanuelle, Simonet, Michel, Toone, Eric J., Zhou, Pei, Sebbane, Florent, and Nacy, Carol A. Tue . "Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC". United States. doi:10.1128/mBio.00674-17.
@article{osti_1399138,
title = {Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC},
author = {Lemaître, Nadine and Liang, Xiaofei and Najeeb, Javaria and Lee, Chul-Jin and Titecat, Marie and Leteurtre, Emmanuelle and Simonet, Michel and Toone, Eric J. and Zhou, Pei and Sebbane, Florent and Nacy, Carol A.},
abstractNote = {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 effectivein vitroagainst 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 bacteriumYersinia 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. IMPORTANCEThe 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 activein vitroagainst 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 byY. pestisand by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.},
doi = {10.1128/mBio.00674-17},
journal = {mBio (Online)},
issn = {2150-7511},
number = 4,
volume = 8,
place = {United States},
year = {2017},
month = {7}
}