Erythromycin leads to differential protein expression through differences in electrostatic and dispersion interactions with nascent proteins
Open accessAbstract
The antibiotic activity of erythromycin, which reversibly binds to a site within the bacterial ribosome exit tunnel, against many gram positive microorganisms indicates that it effectively inhibits the production of proteins. Similar to other macrolides, the activity of erythromycin is far from universal, as some peptides can bypass the macrolide-obstructed exit tunnel and become partially or fully synthesized. It is unclear why, at the molecular level, some proteins can be synthesized while others cannot. Here, we use steered molecular dynamics simulations to examine how erythromycin inhibits synthesis of the peptide ErmCL but not the peptide H-NS. By pulling these peptides through the exit tunnel of the E.coli ribosome with and without erythromycin present, we find that erythromycin directly interacts with both nascent peptides, but the force required for ErmCL to bypass erythromycin is greater than that of H-NS. The largest forces arise three to six residues from their N-terminus as they start to bypass Erythromycin. Decomposing the interaction energies between erythromycin and the peptides at this point, we find that there are stronger electrostatic and dispersion interactions with the more C-terminal residues of ErmCL than with H-NS. These results suggest that erythromycin slows or stalls synthesis of ErmCL compared to H-NS due to stronger interactions with particular residue positions along the nascent protein.
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ERY is an exit tunnel inhibitor that inhibits protein synthesis by altering 23S rRNA and inducing ribosome stalling.
“ERY, acknowledged as an exit tunnel inhibitor, seems to synergistically collaborate with macrolides, culminating in the inhibition of protein synthesis and consequential alterations to the ribosomal nucleotides ARN 23S, thereby inducing ribosome stalling, as proposed by Nguyen et al. (2018).”
From Integrated morpho-physiological and biochemical description of the mechanisms leading stress responses in cyanobacteria (Arthrospira platensis) upon exposure to Erythromycin (2025) · cites this paper as Nguyen et al. (2018)
The Abstract and Introduction say erythromycin binds in the exit tunnel, inhibits synthesis of some proteins, and can cause peptide-dependent ribosome stalling. The Introduction says the exit tunnel—not erythromycin—can act synergistically with macrolides. It also describes possible changes to ribosomal nucleotides during inhibition, but does not establish that erythromycin alters 23S rRNA to induce stalling; the 23S rRNA mutations it discusses confer macrolide resistance. (LLM, conf=0.88)
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- Authors
- Nguyen, H. L., Pham, D. L., O’Brien, E. P., & Li, M. S.
- Affiliations
- Institute for Computational Science and Technology (VN)
- Pennsylvania State University (US)
- Institute of Physics (PL)
- Corresponding author
- O’Brien, Edward P.
- Li, Mai Suan
- Venue
- Scientific Reports
- Published
- 2018-04-24
- Volume
- 8
- Issue
- 1
- Pages
- 6460-6460
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5915450
- OpenAlex
- W2804010971
- Cited by
- 12
- References
- 34
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 1 · 2020: 1 · 2019: 2
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Science Foundation (1553291)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Keywords
- erythromycin, macrolide antibiotics, ribosome exit tunnel, nascent polypeptide chains, H-NS, protein synthesis inhibition, electrostatic interactions, dispersion interactions, antibiotic resistance, Escherichia coli ribosome, steered molecular dynamics
- MeSH terms
- Anti-Bacterial Agents, Erythromycin, Escherichia coli, Peptide Biosynthesis, Peptides, Protein Synthesis Inhibitors, Proteins, Ribosomes, Protein Biosynthesis, Escherichia coli Proteins, Static Electricity, Molecular Dynamics Simulation
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