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Mechanisms of fusidic acid resistance
Adrián González-López1,2, Maria Selmer1,2
1Department of Cell and Molecular Biology, Uppsala University, BMC, P.O. Box 596, SE-75124 Uppsala, Sweden.
Abstract:
Fusidic acid (FA) is an antibiotic used to treat staphylococcal infections, particularly Staphylococcus aureus. It acts by inhibiting protein synthesis through locking elongation factor G (EF-G) to the ribosome. In S. aureus, there are three mechanisms of resistance. Mutations in the antibiotic target, EF-G (fusA), are common. These mutations affect the FA binding or the stability of the FA-locked state of EF-G but, due to effects on the normal function of EF-G, impose a fitness cost for the pathogen. The most common mechanism, FusB-type, involves expression of a resistance protein, FusB or FusC (FusD or FusF in other staphylococci), that provides target protection. The resistance protein binds to EF-G in its FA-locked state and mediates its release from the ribosome. An uncommon resistance mechanism (FusE) involves mutations in a ribosomal protein, uL6. In other bacteria, outside of its current clinical use, resistance to FA involves efflux pumps, limited membrane permeability, or enzymes that chemically alter FA. On a global level, the prevalence of FA resistance is relatively low, indicating that the antibiotic remains effective.
Insights
Fusidic acid effectively treats staphylococcal infections by inhibiting protein synthesis. Resistance mechanisms in Staphylococcus aureus include target mutations, protective proteins, and ribosomal alterations, but overall resistance remains low globally.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Resistance
Background:
- Fusidic acid (FA) is a crucial antibiotic for treating staphylococcal infections, especially those caused by Staphylococcus aureus.
- FA functions by inhibiting bacterial protein synthesis via binding to elongation factor G (EF-G) on the ribosome.
Purpose of the Study:
- To elucidate the mechanisms of resistance to fusidic acid in Staphylococcus aureus.
- To review global prevalence and effectiveness of fusidic acid.
Main Methods:
- Analysis of genetic mutations in EF-G (fusA) and ribosomal protein uL6.
- Investigation of resistance proteins (FusB-type) that protect the EF-G-ribosome complex.
- Review of resistance mechanisms in other bacteria, including efflux pumps and enzymatic inactivation.
Main Results:
- Common resistance arises from EF-G mutations (fusA), which confer a fitness cost.
- The prevalent FusB-type resistance involves proteins that release FA-bound EF-G from the ribosome.
- An uncommon mechanism (FusE) involves mutations in ribosomal protein uL6.
Conclusions:
- Multiple resistance mechanisms exist in S. aureus, balancing effectiveness with pathogen adaptation.
- Fusidic acid remains clinically effective globally due to relatively low resistance prevalence.
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