ArticleNature communications2021
Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 21 citations in OpenAlex.
- Synthesis of tetrahydroisoquinoline-fused polycyclic heterocyclic skeletons via Vilsmeier-reagent promoted decarbonylative annulation.Communications chemistry · 2026Article
- Emerging antibiotic resistance by various novel proteins/enzymes.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Review
- Chemotype- and Target-Driven Genome Mining for a New Natural Product Inhibitor of Bacterial Peptide Deformylase.Journal of the American Chemical Society · 2025Article
- Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism.Nature chemistry · 2025Article
- Expanding the repertoire of imine reductases by mining divergent biosynthetic pathways for promiscuous reactivity.Chem catalysis · 2024Article
- Intracellularly driven chemical modifications of antimicrobial secondary metabolites: Potent mechanisms of self-resistance.Pharmaceutical science advances · 2024Review
- An NmrA-like enzyme-catalysed redox-mediated Diels-Alder cycloaddition with anti-selectivity.Nature chemistry · 2023Article
- Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis.Acta pharmaceutica Sinica. B · 2023Article
- Newly Discovered Mechanisms of Antibiotic Self-Resistance with Multiple Enzymes Acting at Different Locations and Stages.Antibiotics (Basel, Switzerland) · 2022Review
- Biosynthesis of DNA-Alkylating Antitumor Natural Products.Molecules (Basel, Switzerland) · 2022Review
- Potent Antibiotic Lemonomycin: A Glimpse of Its Discovery, Origin, and Chemical Synthesis.Molecules (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antibiotic resistance is becoming one of the major crises, among which hydrolysis reaction is widely employed by bacteria to destroy the reactive pharmacophore. Correspondingly, antibiotic producer has canonically co-evolved this approach with the biosynthetic capability for self-resistance. Here we discover a self-defense strategy featuring with reductive inactivation of hemiaminal pharmacophore by short-chain dehydrogenases/reductases (SDRs) NapW and homW, which are integrated with the naphthyridinomycin biosynthetic pathway. We determine the crystal structure of NapW·NADPH complex and propose a catalytic mechanism by molecular dynamics simulation analysis. Additionally, a similar detoxification strategy is identified in the biosynthesis of saframycin A, another member of tetrahydroisoquinoline (THIQ) antibiotics. Remarkably, similar SDRs are widely spread in bacteria and able to inactive other THIQ members including the clinical anticancer drug, ET-743. These findings not only fill in the missing intracellular events of temporal-spatial shielding mode for cryptic self-resistance during THIQs biosynthesis, but also exhibit a sophisticated damage-control in secondary metabolism and general immunity toward this family of antibiotics.
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