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. 2024 Sep 5;32(9):1429-1442.e6.
doi: 10.1016/j.str.2024.06.013. Epub 2024 Jul 16.

Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity

Zahra Batool  1 , Julia A Pavlova  2 , Madhura N Paranjpe  1 , Andrey G Tereshchenkov  2 , Dmitrii A Lukianov  3 , Ilya A Osterman  3 , Alexey A Bogdanov  4 , Natalia V Sumbatyan  5 , Yury S Polikanov  6
Affiliations

Berberine analog of chloramphenicol exhibits a distinct mode of action and unveils ribosome plasticity

Zahra Batool et al. Structure. .

Abstract

Chloramphenicol (CHL) is an antibiotic targeting the peptidyl transferase center in bacterial ribosomes. We synthesized a new analog, CAM-BER, by substituting the dichloroacetyl moiety of CHL with a positively charged aromatic berberine group. CAM-BER suppresses bacterial cell growth, inhibits protein synthesis in vitro, and binds tightly to the 70S ribosome. Crystal structure analysis reveals that the bulky berberine group folds into the P site of the peptidyl transferase center (PTC), where it competes with the formyl-methionine residue of the initiator tRNA. Our toe-printing data confirm that CAM-BER acts as a translation initiation inhibitor in stark contrast to CHL, a translation elongation inhibitor. Moreover, CAM-BER induces a distinct rearrangement of conformationally restrained nucleotide A2059, suggesting that the 23S rRNA plasticity is significantly higher than previously thought. CAM-BER shows potential in avoiding CHL resistance and presents opportunities for developing novel berberine derivatives of CHL through medicinal chemistry exploration.

Keywords: NPET; PTC; X-ray; affinity; antibiotic; berberine; chloramphenicol; ribosome; translation inhibitor.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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