ArticleScientific reports2019
Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 31 citations in OpenAlex.
- Lipopolysaccharide: Recent Advances in Its Biosynthesis and Controlling Cell Envelope Homeostasis.International journal of molecular sciences · 2025Article
- Inhibiting Lipopolysaccharide Biogenesis: The More You Know the Further You Go.Annual review of biochemistry · 2025Review
- Exploring marine-derived bioactive compounds for dual inhibition of Pseudomonas aeruginosa LpxA and LpxD: integrated bioinformatics and cheminformatics approaches.Molecular diversity · 2025Article
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- Unveiling Therapeutic Potential: TargetingInternational journal of molecular sciences · 2024Article
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections.Nature reviews. Drug discovery · 2023Review
- Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance.Biochimica et biophysica acta. Molecular cell research · 2023Review
- Identification and prioritization of potential therapeutic molecules against LpxA fromCurrent research in structural biology · 2023Article
- Making a chink in their armor: Current and next-generation antimicrobial strategies against the bacterial cell envelope.Advances in microbial physiology · 2023Article
- Using Structure-guided Fragment-Based Drug Discovery to TargetFrontiers in molecular biosciences · 2022Review
- Investigating the Functional Role of Hypothetical Proteins From an Antarctic BacteriumFrontiers in genetics · 2022Article
- 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
- Concepts and Core Principles of Fragment-Based Drug Design.Molecules (Basel, Switzerland) · 2019Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. We report the discovery of multiple small molecule ligands that bind to P. aeruginosa LpxA and LpxD, including dual-binding ligands. Binding poses were determined for select compounds by X-ray crystallography. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function.
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