Complex long-distance effects of mutations that confer linezolid resistance in the large ribosomal subunit

Area of Science:

• Molecular Biology
• Structural Biology
• Computational Chemistry

Background:

• Emerging multidrug-resistant pathogens necessitate novel antibiotic strategies.
• Linezolid, an oxazolidinone antibiotic, faces resistance due to ribosomal nucleotide mutations.
• Understanding atomistic mechanisms of remote mutation effects on antibiotic binding is crucial.

Purpose of the Study:

• To elucidate the atomistic mechanisms by which remote ribosomal mutations confer linezolid resistance.
• To identify key nucleotides mediating long-distance effects from mutation sites to the antibiotic binding pocket.
• To explore information transfer pathways and synergistic effects between mutations.

Main Methods:

• Molecular dynamics simulations to analyze ribosomal dynamics and mutations.
• Free energy calculations to quantify binding affinities.
• Comparative crystallographic studies to inform hypotheses.

Main Results:

• The G2032A-C2499A double mutation confers linezolid resistance via effects percolating to the binding site.
• Nucleotides U2504 and C2452 were identified as key mediators of linezolid binding.
• Two primary information transfer routes and cross-talk between mutations were observed.

Conclusions:

• Remote ribosomal mutations induce complex structural and energetic changes affecting linezolid binding.
• Understanding these long-distance effects is vital for designing next-generation oxazolidinones.
• Synergistic effects of mutations arise indirectly through interconnected pathways.