Extensive natural variation in bacterial ribosomal drug-binding sites

Area of Science:

• Microbiology
• Evolutionary Biology
• Drug Discovery

Background:

• Bacterial ribosomes have drug-binding sites crucial for antibiotic action.
• Divergent drug-binding sites in bacteria can lead to natural antibiotic resistance or hypersensitivity.
• Previous studies lacked systematic analysis of this divergence across bacterial species.

Purpose of the Study:

• To reconstruct the evolutionary history of drug-binding residues in bacterial ribosomes.
• To determine the prevalence of divergent ribosomal drug-binding sites across bacterial species.
• To understand the implications of this diversity for antibiotic resistance and development.

Main Methods:

• Phylogenetic reconstruction of evolutionary history for rRNA drug-binding residues.
• Comparative analysis of ribosomal drug-binding site structures across diverse bacterial lineages.
• Phenotypic assessment of antibiotic resistance in bacteria with divergent sites.

Main Results:

• Many residues considered bacterial-specific are conserved only in subsets of bacteria.
• Divergent ribosomal drug-binding sites are widespread, stemming from ancient rRNA polymorphisms.
• Bacteria with divergent sites exhibit intrinsic resistance to relevant ribosome-targeting antibiotics.

Conclusions:

• Bacterial ribosome drug-binding sites exhibit extensive lineage-specific diversity.
• This diversity arises from conserved polymorphisms at the drug-binding interface.
• Findings provide a resource for developing targeted antibiotics and personalized pathogen treatment strategies.