Mycobacterial mistranslation is necessary and sufficient for rifampicin phenotypic resistance

Area of Science:

• Microbiology
• Molecular Biology
• Genetics

Background:

• Biological systems naturally contain errors, with protein translation being a frequent source.
• Protein mistranslation generates diverse protein quasi-species, with potential for novel phenotypes.
• The impact of varying mistranslation rates on organismal phenotypes remains largely unexplored.

Purpose of the Study:

• To investigate the phenotypic consequences of altered protein translation fidelity in mycobacteria.
• To determine if specific amino acid substitutions during translation affect antibiotic susceptibility.
• To explore the potential of translational errors as a mechanism for environmental adaptation.

Main Methods:

• Culturing mycobacteria under specific growth conditions to induce amino acid substitutions.
• Quantifying the rates of glutamate for glutamine and aspartate for asparagine substitutions.
• Assessing the phenotypic resistance and susceptibility to rifampicin at varying mistranslation rates.
• Evaluating the differential susceptibility of RNA polymerase to rifampicin.

Main Results:

• Mycobacteria exhibit high rates of glutamate for glutamine and aspartate for asparagine substitutions under certain conditions.
• Increased rates of these amino acid substitutions correlate with significant phenotypic resistance to rifampicin.
• Decreased mistranslation rates result in increased susceptibility to rifampicin.
• Observed phenotypic changes are linked to altered susceptibility of RNA polymerase to the drug.

Conclusions:

• Altering translational fidelity, through specific amino acid substitutions, is a viable mechanism for generating antibiotic resistance in mycobacteria.
• This process represents a unique form of environmental adaptation, where changes in protein accuracy influence survival.
• The findings highlight the potential of modulating translational fidelity as a strategy to combat drug resistance.