ArticleNature chemical biology2024
Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Sparsomycin inhibits translation through a conserved mechanism across all domains of life.Nucleic acids research · 2026Article
- Benzoxaborole-modified azithromycins inhibit translation without inducingAntimicrobial agents and chemotherapy · 2026Article
- Capturing ribosomal structures in cellular extracts with cryoPRISM: A purification-free cryoEM approach reveals novel structural states.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Anti-infective macrozones: design, biological evaluation and structure-activity relationships.ADMET & DMPK · 2026Article
- Heteroaryl Bishydrazono Nitroimidazoles: A Unique Structural Skeleton with Potent Multitargeting Antibacterial Activity.International journal of molecular sciences · 2025Article
- Hybrid Antibiotics Targeting the Bacterial Ribosome.ACS central science · 2025Article
- Structural insights into context-specific inhibition of bacterial translation by macrolides.Nature communications · 2025Article
- Selective silencing of antibiotic-tethered ribosomes as a resistance mechanism against aminoglycosides.Nature communications · 2025Article
- Exploring GNRA tetraloop-like motifs in nucleic acid 3D structures.Scientific reports · 2025Article
- Resensitizing the Untreatable: Zidovudine and Polymyxin Combinations to Combat Pan-Drug-ResistantPharmaceuticals (Basel, Switzerland) · 2025Article
- Nanomotion technology for testing azithromycin susceptibility ofMicrobiology spectrum · 2025Article
- Exploring the antibacterial and anti-biofilm properties of Diacerein against methicillin-resistantFrontiers in microbiology · 2025Article
- Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014-2024).Frontiers in microbiology · 2025Review
- Evading resistance at the double.Nature chemical biology · 2024Article
- Primed for Discovery.Biochemistry · 2024Review
- War and peace: exploring microbial defence systems as a source of new antimicrobial therapies.Frontiers in pharmacology · 2024Review
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Authors and funding
8 authors.
Funding
Abstract
Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.
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