Ribosomal Mechanisms in Antibiotic Resistance

The bacterial ribosome, a complex molecular machine responsible for protein synthesis, is the target of many clinically important antibiotics. Resistance arises through a variety of ribosomal mechanisms that alter drug binding or bypass inhibition. These include chemical modification of ribosomal RNA by methyltransferases, structural remodelling of the peptidyl transferase centre or exit tunnel, and active ribosomal protection by specialised proteins. In some pathogens, mutations in ribosomal proteins or rRNA nucleotides reduce antibiotic affinity without compromising translation fidelity. Other bacteria deploy ATP-binding cassette F (ABCF) proteins to displace bound antibiotics and restore peptidyl transferase activity. Nascent peptide-mediated stalling also regulates expression of resistance determinants by altering the conformation of the exit tunnel in response to macrolides. Recent structural and biochemical studies have illuminated how combinations of antibiotics can act synergistically at distinct ribosomal sites, offering new avenues to overcome resistance. Understanding these mechanisms is essential for guiding the design of next-generation antimicrobials and combination therapies with improved efficacy against multidrug-resistant pathogens.

Research from Nature Portfolio

Recent studies have provided high-resolution snapshots of antibiotic–ribosome interactions under physiologically relevant conditions. In 2023, X-ray crystallography of Erm-methylated 70S ribosomes revealed how hygromycin A cooperatively stabilises macrolide binding in the exit tunnel, overcoming methyltransferase-mediated resistance and slowing antibiotic dissociation. This work has laid the groundwork for engineering synergistic antibiotic pairs with enhanced bactericidal properties. A complementary investigation in 2021 combined cryo-EM and molecular dynamics to elucidate the sequence-specific arrest induced by erythromycin and telithromycin at charged Arg/Lys-rich motifs. This study unveiled the structural basis for context-dependent stalling and its role in activating resistance gene expression, thereby informing rational modifications to macrolide scaffolds to evade resistance.

Ribosomal Mechanisms in Antibiotic Resistance publication trend

The graph below shows the total number of articles in ribosomal mechanisms in antibiotic resistance across all publications each year (not limited to Nature Index journals).

Technical terms

Ribosome: A macromolecular complex of RNA and protein that orchestrates the translation of messenger RNA into polypeptides.

Peptidyl transferase centre (PTC): The catalytic site within the large ribosomal subunit where peptide bonds are formed between amino acids.

Nascent peptide exit tunnel (NPET): A conduit through which the growing peptide chain traverses before emerging from the ribosome, often targeted by tunnel-binding antibiotics.

ABCF proteins: A subfamily of ATP-binding cassette proteins that confer antibiotic resistance by directly interacting with the ribosome and displacing bound drugs.

Erm methylation: The enzymatic dimethylation of a specific adenine in 23S rRNA that reduces binding of macrolide, lincosamide and streptogramin antibiotics.

References

1. Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A. Nature Communications (2023).
2. Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics. Nature Communications (2021).
3. Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria: VmlR2, Ard1 and CplR. Nucleic Acids Research (2023).
4. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. Journal of the American Chemical Society (2023).
5. ABC-F Proteins Mediate Antibiotic Resistance through Ribosomal Protection. mBio (2016).