# Structure-Guided Semisynthesis of Blasticidin S–Amicetin Chimeras as Selective Ribosome Inhibitors

## TL;DR

Scientists created new antibiotic compounds by combining two natural products, making them more selective against bacteria and less harmful to human cells.

## Contribution

A structure-guided semisynthetic approach to create blasticidin S–amicetin chimeras with improved antibacterial selectivity.

## Key findings

- Four C6′ classes of chimeras were synthesized with high efficiency and yields up to 38%.
- Phenethyl amide series showed >256 μg/mL mammalian cytotoxicity and selectivity indices >50.
- Structural analysis explained the selectivity via bacterial-specific ribosome pocket engagement.

## Abstract

Peptidyl nucleosides are broad-acting inhibitors, but
their dense
functionality and complex reactivity have historically limited the
modification of these scaffolds. Guided by structural overlays and
molecular modeling, we designed blasticidin S-amicetin chimeras to
exploit a bacterial-specific pocket of the ribosomal PTC while reducing
eukaryotic ribosome engagement. To test this hypothesis, we developed
a semisynthetic route enabling sequential C6′ derivatization
and C4 amine coupling on the blasticidin S scaffold, facilitated by
counterion exchange to prevent side reactions. This approach furnished
four C6′ classes (acid, methyl ester, primary amide, phenethyl
amide), each diversified at C4 with para-aminobenzoate
motifs, delivering densely functionalized chimeras in as few as four
steps and up to 38% yield. Across the series, antibacterial potency
was retained while mammalian cytotoxicity dropped sharply, with selectivity
indices approaching >50 and cytotoxicity values >256 μg/mL
for
the phenethyl amide series. Comparison of resolved ribosome structures
supplemented by modeling rationalizes the observed selectivity gains
as engagement of a termination-compatible bacterial pocket that is
disfavored during eukaryotic elongation. These results demonstrate
how structure-guided semisynthesis can transform a challenging natural
product into selective translation inhibitors and establish a practical
framework for diversifying chemically complex scaffolds.