ArticleProceedings of the National Academy of Sciences of the United States of America2021
THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 23 citations in OpenAlex.
- Tetrahydrocarbazole as a Versatile Scaffold in Drug Discovery: A Cross-Target SAR Analysis and Design Paradigms.Molecules (Basel, Switzerland) · 2026Review
- Bacterial cell envelope-targeting antibiotics.Nature reviews. Microbiology · 2026Review
- Novel antimicrobial 3-phenyl-4-phenoxypyrazole derivatives target cell wall lipid intermediates with low mammalian cytotoxicity.Scientific reports · 2025Article
- Trans-kingdom conservation of mechanism between bacterial actifensin and eukaryotic defensins.npj antimicrobials and resistance · 2025Article
- Streptococcus pneumoniae epidemiology, pathogenesis and control.Nature reviews. Microbiology · 2025Review
- The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding.Journal of the American Chemical Society · 2024Article
- The impact of oxygen content onFrontiers in microbiology · 2024Article
- Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria.Journal of medicinal chemistry · 2023Article
- High-Throughput Screening of Natural Product and Synthetic Molecule Libraries for Antibacterial Drug Discovery.Metabolites · 2023Review
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Emerging antibiotic resistance demands identification of novel antibacterial compound classes. A bacterial whole-cell screen based on pneumococcal autolysin-mediated lysis induction was developed to identify potential bacterial cell wall synthesis inhibitors. A hit class comprising a 1-amino substituted tetrahydrocarbazole (THCz) scaffold, containing two essential amine groups, displayed bactericidal activity against a broad range of gram-positive and selected gram-negative pathogens in the low micromolar range. Mode of action studies revealed that THCz inhibit cell envelope synthesis by targeting undecaprenyl pyrophosphate-containing lipid intermediates and thus simultaneously inhibit peptidoglycan, teichoic acid, and polysaccharide capsule biosynthesis. Resistance did not readily develop in vitro, and the ease of synthesizing and modifying these small molecules, as compared to natural lipid II-binding antibiotics, makes THCz promising scaffolds for development of cell wall-targeting antimicrobials.
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