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

Lemaître, Nadine; Liang, Xiaofei; Najeeb, Javaria; Lee, Chul‐Jin; Titécat, Marie; Leteurtre, Emmanuelle; Simonet, Michel; Toone, Eric J.; Zhou, Pei; Sebbane, Florent

doi:10.1128/mbio.00674-17

Cited by 26 publications

(23 citation statements)

References 37 publications

(52 reference statements)

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“…Inhibition of LpxC increases the antibiotic susceptibility of A. baumannii (107), including XDR clinical isolates (108). The MIC 50/90 values of a new LpxC inhibitor were 0.8/3.2 g/ml (MIC range, 0.5 to Ն64 g/ml) when tested on 25 clinical A. baumannii isolates, including 19 MDR/XDR strains (7 OXA-23 producers and 1 OXA-40 producer) (109). An LpxC inhibitor, ACHN-975, failed human trials due to inflammation at the infusion site.…”

Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

256

179

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Carbapenem-resistantAcinetobacter baumannii(CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.

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Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

256

179

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“…At 37°C, a very clear zone of growth rescue occurred for both fatty acid and LPS inhibitors. However, only CHIR-090 and compound 1, a recently published hydroxamic acid LpxC inhibitor [ 20 ], were able to rescue growth at 30°C, demonstrating a differential growth rescue effect at 30°C compared to 37°C via these two pathways ( Fig 3 ). Although the reason for this is not understood, it can serve as a convenient way to distinguish between inhibitors of the lipid A and fatty acid biosynthesis pathways.…”

Section: Resultsmentioning

confidence: 94%

A pathway-directed positive growth restoration assay to facilitate the discovery of lipid A and fatty acid biosynthesis inhibitors in Acinetobacter baumannii

et al. 2018

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Acinetobacter baumannii ATCC 19606 can grow without lipooligosaccharide (LOS). Lack of LOS can result from disruption of the early lipid A biosynthetic pathway genes lpxA, lpxC or lpxD. Although LOS itself is not essential for growth of A. baumannii ATCC 19606, it was previously shown that depletion of the lipid A biosynthetic enzyme LpxK in cells inhibited growth due to the toxic accumulation of lipid A pathway intermediates. Growth of LpxK-depleted cells was restored by chemical inhibition of LOS biosynthesis using CHIR-090 (LpxC) and fatty acid biosynthesis using cerulenin (FabB/F) and pyridopyrimidine (acetyl-CoA-carboxylase). Here, we expand on this by showing that inhibition of enoyl-acyl carrier protein reductase (FabI), responsible for converting trans-2-enoyl-ACP into acyl-ACP during the fatty acid elongation cycle also restored growth during LpxK depletion. Inhibition of fatty acid biosynthesis during LpxK depletion rescued growth at 37°C, but not at 30°C, whereas rescue by LpxC inhibition was temperature independent. We exploited these observations to demonstrate proof of concept for a targeted medium-throughput growth restoration screening assay to identify small molecule inhibitors of LOS and fatty acid biosynthesis. The differential temperature dependence of fatty acid and LpxC inhibition provides a simple means by which to separate growth stimulating compounds by pathway. Targeted cell-based screening platforms such as this are important for faster identification of compounds inhibiting pathways of interest in antibacterial discovery for clinically relevant Gram-negative pathogens.

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“…These compounds interact with LpxC at the level of the so‐called “hydrophobic passage” given their similarity in size and shape with the acyl chains of endogenous fatty acids. These molecules not only display activity against multidrug‐resistant strains but also demonstrate to be efficacious in the cure of plague, a severe infection caused by Y. pestis . These novel LpxC targeting compounds may therefore represent therapeutically attractive molecules.…”

Section: Targeting Lps Biogenesis Pathway For the Discovery Of Novel mentioning

confidence: 99%

Fat Matters for Bugs: How Lipids and Lipid Modifications Make the Difference in Bacterial Life

Sperandeo

Polissi

Fabiani

2019

Euro J Lipid Sci & Tech

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Lipids are building blocks of biological membranes in the three domains of life and are endowed with several important biological functions. Lipopolysaccharide (LPS) is a peculiar glycolipid that represents the hallmark of the cell envelope of Gram‐negative bacteria, a group comprising several important human pathogens. The presence of LPS in the outer membrane (OM) of Gram‐negative bacteria correlates not only with the intrinsic resistance of this group of bacteria toward several antibiotics currently in use, but also with the worrisome increase in antibiotic resistance that is depleting the arsenal of efficacious molecules to cure bacterial infections. LPS consists of a conserved internal moiety decorated by a more variable distal unit. Several modifications occur at the canonical LPS structure during bacterial infection which are exploited by the microorganism to co‐evolve with the host thus evading its immune system. This viewpoint article discusses the current knowledge on LPS biogenesis and modification systems and their consequences on recognition by immune cells and antimicrobial resistance. It also discusses how knowledge on LPS biogenesis can be exploited to develop molecules able to dismantle the Gram‐negative protective barrier and to interfere with the interaction with the mammalian host. Practical Applications: Antibiotic resistance is a major threat for human health leading to inefficacy of many antibiotics to treat infectious diseases. Resistance to antibiotics causes around 25 000 deaths per year in the European Union alone and 700 000 deaths per year globally. This results in an increase of 1.5 billion euros per year in healthcare costs and productivity losses for illness. Gram‐negative bacteria are intrinsically resistant to many antibiotics, due to their LPS‐coated cell surface that protects them from the environment. LPS is sensed by the host immune system as a signal of bacterial infection, moreover bacteria exploit the complexity of LPS modifications to modulate the host immune response and eventually escape it. A deep understanding of the molecular mechanisms underlying LPS biogenesis, including the physico‐chemical and biological consequences of its lipid modifications, will be instrumental to develop novel antibiotic treatments aimed at dismantling the Gram‐negative bacteria barrier and restoring drug sensitivity. The hallmark of Gram‐negative bacteria is the presence of an asymmetric outer membrane (OM) surrounding the cytoplasmic membrane (inner membrane, IM), whose outer leaflet is made by lipopolysaccharide (LPS). A layer of peptidoglycan (PG) is sandwiched in between. LPS endows the bacteria with increased resistance to many antibiotics and is the first line of interaction with the host cell immune system. Chemical modifications of the canonical LPS structure determine different stimulatory effects of the immune response and allow the bacteria to escape from the killing action of effector molecules such as antimicrobial peptides.

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

Cited by 26 publications

References 37 publications

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

A pathway-directed positive growth restoration assay to facilitate the discovery of lipid A and fatty acid biosynthesis inhibitors in Acinetobacter baumannii

Fat Matters for Bugs: How Lipids and Lipid Modifications Make the Difference in Bacterial Life

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