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Fusidic acid resistance through changes in the dynamics of the drug target
Jennifer H Tomlinson1,2, Arnout P Kalverda3,2, Antonio N Calabrese3,2
1School of Molecular and Cellular Biology, University of Leeds, LS2 9JT Leeds, United Kingdom; j.h.tomlinson@leeds.ac.uk.
Abstract:
Antibiotic resistance in clinically important bacteria can be mediated by target protection mechanisms, whereby a protein binds to the drug target and protects it from the inhibitory effects of the antibiotic. The most prevalent source of clinical resistance to the antibiotic fusidic acid (FA) is expression of the FusB family of proteins that bind to the drug target (Elongation factor G [EF-G]) and promote dissociation of EF-G from FA-stalled ribosome complexes. FusB binding causes changes in both the structure and conformational flexibility of EF-G, but which of these changes drives FA resistance was not understood. We present here detailed characterization of changes in the conformational flexibility of EF-G in response to FusB binding and show that these changes are responsible for conferring FA resistance. Binding of FusB to EF-G causes a significant change in the dynamics of domain III of EF-GC3 that leads to an increase in a minor, more disordered state of EF-G domain III. This is sufficient to overcome the steric block of transmission of conformational changes within EF-G by which FA prevents release of EF-G from the ribosome. This study has identified an antibiotic resistance mechanism mediated by allosteric effects on the dynamics of the drug target.
Insights
FusB proteins confer fusidic acid resistance by altering Elongation factor G (EF-G) dynamics, not just structure. This change in EF-G flexibility allows bacteria to overcome antibiotic inhibition.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Antibiotic resistance is a major global health threat.
- Target protection is a key bacterial resistance mechanism.
- Fusidic acid resistance often involves FusB proteins binding Elongation factor G (EF-G).
Purpose of the Study:
- To elucidate the precise mechanism by which FusB proteins confer fusidic acid resistance.
- To determine whether structural changes or altered dynamics of EF-G are responsible for resistance.
Main Methods:
- Detailed characterization of EF-G conformational flexibility upon FusB binding.
- Analysis of EF-G dynamics using biophysical techniques (specific techniques not detailed in abstract).
Main Results:
- FusB binding induces significant changes in the conformational flexibility of EF-G domain III.
- These dynamic changes lead to an increased population of a disordered EF-G domain III state.
- This altered flexibility is sufficient to disrupt the inhibitory complex formed by fusidic acid and EF-G on the ribosome.
Conclusions:
- Antibiotic resistance to fusidic acid is mediated by allosteric effects on the dynamics of the drug target, EF-G.
- Altered conformational flexibility of EF-G, rather than just structural changes, is the key driver of fusidic acid resistance.
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