ArticleJournal of molecular biology2009
Recombineering reveals a diverse collection of ribosomal proteins L4 and L22 that confer resistance to macrolide antibiotics.
Article in Journal of molecular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 56 citations in OpenAlex.
- Novel features ofMicrobial genomics · 2026Article
- Multiple Mechanisms Confer Resistance to Azithromycin inMicrobiology spectrum · 2022Article
- Decreased Susceptibility ofThe Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale · 2022Article
- A Survey of Spontaneous Antibiotic-Resistant Mutants of the Halophilic, Thermophilic BacteriumAntibiotics (Basel, Switzerland) · 2021Article
- Evidence of Horizontal Gene Transfer of 50S Ribosomal GenesFrontiers in microbiology · 2021Article
- Increased power from conditional bacterial genome-wide association identifies macrolide resistance mutations in Neisseria gonorrhoeae.Nature communications · 2020Article
- Investigation of Macrolide Resistance Genotypes inPathogens (Basel, Switzerland) · 2020Article
- Exit tunnel modulation as resistance mechanism of S. aureus erythromycin resistant mutant.Scientific reports · 2019Article
- Azithromycin resistance levels and mechanisms in Escherichia coli.Scientific reports · 2019Article
- Carrion's Disease: the Sound of Silence.Clinical microbiology reviews · 2018Review
- Rotational restriction of nascent peptides as an essential element of co-translational protein folding: possible molecular players and structural consequences.Biology direct · 2017Article
- Ribosomal Mutations Conferring Macrolide Resistance in Legionella pneumophila.Antimicrobial agents and chemotherapy · 2017Article
- Review
- Development and characterisation of highly antibiotic resistant Bartonella bacilliformis mutants.Scientific reports · 2016Article
- The extended loops of ribosomal proteins uL4 and uL22 of Escherichia coli contribute to ribosome assembly and protein translation.Nucleic acids research · 2016Article
- Macrolide Resistance inFrontiers in cellular and infection microbiology · 2016Review
- CdiA from Enterobacter cloacae delivers a toxic ribosomal RNase into target bacteria.Structure (London, England : 1993) · 2014Article
- A defect in ATP-citrate lyase links acetyl-CoA production, virulence factor elaboration and virulence in Cryptococcus neoformans.Molecular microbiology · 2012Article
- Macrolide resistance-associated 23S rRNA mutation in Mycoplasma genitalium, Japan.Emerging infectious diseases · 2011Article
- tmRNA regulates synthesis of the ArfA ribosome rescue factor.Molecular microbiology · 2011Article
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2 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in ribosomal proteins L4 and L22 confer resistance to erythromycin and other macrolide antibiotics in a variety of bacteria. L4 and L22 have elongated loops whose tips converge in the peptide exit tunnel near the macrolide-binding site, and resistance mutations typically affect residues within these loops. Here, we used bacteriophage lambda Red-mediated recombination, or "recombineering," to uncover new L4 and L22 alleles that confer macrolide resistance in Escherichia coli. We randomized residues at the tips of the L4 and L22 loops using recombineered oligonucleotide libraries and selected the mutagenized cells for erythromycin-resistant mutants. These experiments led to the identification of 341 resistance mutations encoding 278 unique L4 and L22 proteins-the overwhelming majority of which are novel. Many resistance mutations were complex, involving multiple missense mutations, in-frame deletions, and insertions. Transfer of L4 and L22 mutations into wild-type cells by phage P1-mediated transduction demonstrated that each allele was sufficient to confer macrolide resistance. Although L4 and L22 mutants are typically resistant to most macrolides, selections carried out on different antibiotics revealed macrolide-specific resistance mutations. L22 Lys90Trp is one such allele that confers resistance to erythromycin but not to tylosin and spiramycin. Purified L22 Lys90Trp ribosomes show reduced erythromycin binding but have the same affinity for tylosin as wild-type ribosomes. Moreover, dimethyl sulfate methylation protection assays demonstrated that L22 Lys90Trp ribosomes bind tylosin more readily than erythromycin in vivo. This work underscores the exceptional functional plasticity of the L4 and L22 proteins and highlights the utility of Red-mediated recombination in targeted genetic selections.
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