ArticleProceedings of the National Academy of Sciences of the United States of America2015
Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Mechanistic insights into 50Science advances · 2025Article
- Structural insights into context-specific inhibition of bacterial translation by macrolides.Nature communications · 2025Article
- Recent Advances in Understanding the Molecular Mechanisms of Multidrug Resistance and Novel Approaches of CRISPR/Cas9-Based Genome-Editing to Combat This Health Emergency.International journal of nanomedicine · 2024Review
- Ribosome-targeting antibiotics and resistanceRSC medicinal chemistry · 2023Review
- Nonribosomal antibacterial peptides isolated from Streptomyces agglomeratus 5-1-3 in the Qinghai-Tibet Plateau.Microbial cell factories · 2023Article
- 16-membered ring macrolides and erythromycin induce ermB expression by different mechanisms.BMC microbiology · 2022Article
- Article
- Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics.Nature communications · 2021Article
- Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.Nature chemical biology · 2021Article
- Potential Target Site for Inhibitors in MLSAntibiotics (Basel, Switzerland) · 2021Article
- Translational Attenuation Mechanism ofFrontiers in microbiology · 2021Article
- Resistome ofACS infectious diseases · 2020Article
- Crystal structure of ErmE - 23S rRNA methyltransferase in macrolide resistance.Scientific reports · 2019Article
- Translational control of antibiotic resistance.Open biology · 2019Review
- How Macrolide Antibiotics Work.Trends in biochemical sciences · 2018Review
- Ribosome-Targeting Antibiotics: Modes of Action, Mechanisms of Resistance, and Implications for Drug Design.Annual review of biochemistry · 2018Review
- Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens.Frontiers in microbiology · 2018Review
- Kinetics of drug-ribosome interactions defines the cidality of macrolide antibiotics.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Co-produced natural ketolides methymycin and pikromycin inhibit bacterial growth by preventing synthesis of a limited number of proteins.Nucleic acids research · 2017Article
- The macrolide antibiotic renaissance.British journal of pharmacology · 2017Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.