ArticlePloS one2016
Toxic Accumulation of LPS Pathway Intermediates Underlies the Requirement of LpxH for Growth of Acinetobacter baumannii ATCC 19606.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 48 citations in OpenAlex.
- Lipopolysaccharide insertion and vesicle mediated turnover drive growth independent outer membrane adaptation in Escherichia coli.Nature communications · 2026Article
- From Obscurity to Opportunity: LpxH Emerges as a Promising Antibiotic Target in the Battle against Gram-Negative Pathogens.ACS infectious diseases · 2025Review
- Chemical genomics informs antibiotic and essential gene function in Acinetobacter baumannii.PLoS genetics · 2025Article
- Article
- Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.Nature microbiology · 2024Article
- Article
- Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance.Biochimica et biophysica acta. Molecular cell research · 2023Review
- Article
- Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.Accounts of chemical research · 2021Review
- Pharmacoinformatics approaches to identify potential hits against tetraacyldisaccharide 4'-kinase (LpxK) ofRSC advances · 2020Article
- Applications of different solvents and conditions for differential extraction of lipopolysaccharide in Gram-negative bacteria.Journal of microbiology (Seoul, Korea) · 2019Article
- Pushing the envelope: LPS modifications and their consequences.Nature reviews. Microbiology · 2019Review
- Substrate specificity of the pyrophosphohydrolase LpxH determines the asymmetry ofThe Journal of biological chemistry · 2019Article
- Structure-Activity Relationship of Sulfonyl Piperazine LpxH Inhibitors Analyzed by an LpxE-Coupled Malachite Green Assay.ACS infectious diseases · 2019Article
- Targeted lipopolysaccharide biosynthetic intermediate analysis with normal-phase liquid chromatography mass spectrometry.PloS one · 2019Article
- Interplay of Klebsiella pneumoniaemSphere · 2018Article
- Cell-based screen for discovering lipopolysaccharide biogenesis inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- New Shuttle Vectors for Gene Cloning and Expression in Multidrug-Resistant Acinetobacter Species.Antimicrobial agents and chemotherapy · 2018Article
- Expanding the paradigm for the outer membrane: Acinetobacter baumannii in the absence of endotoxin.Molecular microbiology · 2018Review
- Structure, inhibition, and regulation of essential lipid A enzymes.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2017Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lipid A moiety of lipopolysaccharide (LPS) is the main constituent of the outer leaflet of the Gram-negative bacterial outer membrane (OM) and is essential in many Gram-negative pathogens. An exception is Acinetobacter baumannii ATCC 19606, where mutants lacking enzymes occurring early in lipid A biosynthesis (LpxA, LpxC or LpxD), and correspondingly lacking LPS, can grow. In contrast, we show here that LpxH, an enzyme that occurs downstream of LpxD in the lipid A biosynthetic pathway, is essential for growth in this strain. Multiple attempts to disrupt lpxH on the genome were unsuccessful, and when LpxH expression was controlled by an isopropyl β-d-1-thiogalactopyranoside (IPTG) inducible promoter, cell growth under typical laboratory conditions required IPTG induction. Mass spectrometry analysis of cells shifted from LpxH-induced to uninduced (and whose growth was correspondingly slowing as LpxH was depleted) showed a large cellular accumulation of UDP-2,3-diacyl-GlcN (substrate of LpxH), a C14:0(3-OH) acyl variant of the LpxD substrate (UDP-3-O-[(R)-3-OH-C14]-GlcN), and disaccharide 1-monophosphate (DSMP). Furthermore, the viable cell counts of the LpxH depleted cultures dropped modestly, and electron microscopy revealed clear defects at the cell (inner) membrane, suggesting lipid A intermediate accumulation was toxic. Consistent with this, blocking the synthesis of these intermediates by inhibition of the upstream LpxC enzyme using CHIR-090 abrogated the requirement for IPTG induction of LpxH. Taken together, these data indicate that LpxH is essential for growth in A. baumannii ATCC19606, because, unlike earlier pathway steps like LpxA or LpxC, blockage of LpxH causes accumulation of detergent-like pathway intermediates that prevents cell growth.
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