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| Title | Structure-function comparison of Arbekacin with other aminoglycosides elucidates its higher potency as bacterial translation inhibitor. |
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| Journal, issue, pages | Sci Rep, Vol. 15, Issue 1, Page 18271, Year 2025 |
| Publish date | May 25, 2025 |
 Authors | Soneya Majumdar / Narayan Prasad Parajuli / Xueliang Ge / Suparna Sanyal /  |
| PubMed Abstract | Aminoglycoside antibiotics are well-known inhibitors of bacterial protein synthesis, which act mainly by inhibiting ribosomal translocation and inducing miscoding errors. Arbekacin (ABK) is a ...Aminoglycoside antibiotics are well-known inhibitors of bacterial protein synthesis, which act mainly by inhibiting ribosomal translocation and inducing miscoding errors. Arbekacin (ABK) is a semisynthetic aminoglycoside that was developed by adding a 3-amino-2-hydroxybutyric (AHB) moiety to the 2-deoxystreptamine (2-DOS) ring of dibekacin for counteracting the problem of enzyme-mediated resistance of aminoglycosides. Here, we have systematically compared the inhibition efficacy of ABK with other aminoglycosides by in vivo MIC determination and in vitro fast-kinetics based translocation and termination assays complemented with a high-resolution cryo-EM structure. ABK presents significantly lower MIC value compared to its parent antibiotics kanamycin and dibekacin. Consistent with that, ABK inhibits translocation with lower inhibition constant and reside on the ribosome for significantly longer time than the classical aminoglycosides. Our 3.1 Å resolution cryo-EM structure of ABK-bound ribosome containing mRNA and initiator-tRNA, shows interactions of the unique AHB moiety of ABK with rRNA nucleobases, which likely provide additional stabilization of ABK at the canonical aminoglycoside binding pocket and contribute to its prolonged dwelling time. Our structural and functional analyses provide molecular basis for higher potency of ABK in bacterial translation inhibition and opens the possibility of rational design of new antibiotics. |
 External links | Sci Rep / PubMed:40415027 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 Å |
| Structure data | EMDB-48329, PDB-9mkk: |
| Chemicals |  ChemComp-84G: |
| Source |
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 Keywords | RIBOSOME/INHIBITOR / ANTIBIOTIC / amino glycoside / arbekacin / Escherichia coli 70S / protein synthesis inhibitor / RIBOSOME / RIBOSOME-INHIBITOR / ANTIBIOTIC complex |
escherichia coli (E. coli)