Hybrid Antibiotics Targeting the Bacterial Ribosome

Antimicrobial resistance remains a formidable challenge
to modern
medicine, with bacterial resistance mechanisms increasingly eroding
the utility of clinically important antibiotics. While recent efforts
have expanded the antibacterial pipeline, the development of resistance
in priority pathogens continues to exceed the pace of new drug development.
One emerging strategy to overcome resistance is the rational design
of hybrid antibiotics that engage multiple binding sites. Here we
describe the design, synthesis, and microbiological and structural
characterization of hybrid antibiotics of azithromycin, tedizolid,
and chloramphenicol that span the peptidyltransferase center (PTC)
and nascent peptide exit tunnel (NPET) in the bacterial ribosome.
We characterize the binding of four such hybrids by cryo-electron
microscopy, granting insight into their molecular mechanisms of action.
We identify a hybrid of azithromycin and tedizolid that is active
against a diverse panel of multidrug-resistant Gram-positive bacteria
and is minimally affected by ribosomal protection (ABC-F) resistance
mechanisms. These results extend our understanding of ribosome inhibition
and provide a pipeline for the rational design of dual-action antibiotics
that target the ribosome. In a broader context, this work offers a
framework for developing bifunctional inhibitors that engage adjacent
binding sites by means of a rational cycle of synthetic optimization,
biological evaluation, and structural characterization.