ArticleBiochemistry2007
Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli.
Article in Biochemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 107 citations in OpenAlex.
- Bioactivity-driven prediction of antibacterial synergy using machine learning models.PLoS computational biology · 2026Article
- Biology of novel LpxC inhibitors forMicrobiology spectrum · 2026Article
- Preserving fermented-foods microbial diversity through systematic culturomics for the discovery of multi-strain probiotic candidates.Current research in food science · 2026Article
- Bacterial cell widening alters periplasmic size and activates envelope stress responses.The EMBO journal · 2025Article
- A co-conserved gene pair supportsJournal of bacteriology · 2025Article
- A co-conserved gene pair supportsbioRxiv : the preprint server for biology · 2025Article
- Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity.Journal of medicinal chemistry · 2024Article
- Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.Nature microbiology · 2024Article
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- A role for the Gram-negative outer membrane in bacterial shape determination.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Antibacterial activities of anthraquinones: structure-activity relationships and action mechanisms.RSC medicinal chemistry · 2023Review
- A role for the Gram-negative outer membrane in bacterial shape determination.bioRxiv : the preprint server for biology · 2023Article
- Microbial Genomics: Innovative Targets and Mechanisms.Antibiotics (Basel, Switzerland) · 2023Review
- Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.Journal of medicinal chemistry · 2022Article
- Adaptive Responses ofAntimicrobial agents and chemotherapy · 2022Article
- Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity.ACS infectious diseases · 2021Article
- Border Control: Regulating LPS Biogenesis.Trends in microbiology · 2021Review
- Direct Observation of Conversion From Walled Cells to Wall-Deficient L-Form andFrontiers in microbiology · 2021Article
- State of the Art in the Culture of the Human Microbiota: New Interests and Strategies.Clinical microbiology reviews · 2020Review
- Application of LpxC enzyme inhibitor to inhibit some fast-growing bacteria in human gut bacterial culturomics.BMC microbiology · 2019Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
The deacetylation of UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine (UDP-3-O-acyl-GlcNAc) by LpxC is the committed reaction of lipid A biosynthesis. CHIR-090, a novel N-aroyl-l-threonine hydroxamic acid, is a potent, slow, tight-binding inhibitor of the LpxC deacetylase from the hyperthermophile Aquifex aeolicus, and it has excellent antibiotic activity against Pseudomonas aeruginosa and Escherichia coli, as judged by disk diffusion assays. We now report that CHIR-090 is also a two-step slow, tight-binding inhibitor of E. coli LpxC with Ki = 4.0 nM, Ki* = 0.5 nM, k5 = 1.9 min-1, and k6 = 0.18 min-1. CHIR-090 at low nanomolar levels inhibits LpxC orthologues from diverse Gram-negative pathogens, including P. aeruginosa, Neisseria meningitidis, and Helicobacter pylori. In contrast, CHIR-090 is a relatively weak competitive and conventional inhibitor (lacking slow, tight-binding kinetics) of LpxC from Rhizobium leguminosarum (Ki = 340 nM), a Gram-negative plant endosymbiont that is resistant to this compound. The KM (4.8 microM) and the kcat (1.7 s-1) of R. leguminosarum LpxC with UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine as the substrate are similar to values reported for E. coli LpxC. R. leguminosarum LpxC therefore provides a useful control for validating LpxC as the primary target of CHIR-090 in vivo. An E. coli construct in which the chromosomal lpxC gene is replaced by R. leguminosarum lpxC is resistant to CHIR-090 up to 100 microg/mL, or 400 times above the minimal inhibitory concentration for wild-type E. coli. Given its relatively broad spectrum and potency against diverse Gram-negative pathogens, CHIR-090 is an excellent lead for the further development of new antibiotics targeting the lipid A pathway.
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