Proteomic Comparison of Ivermectin Sensitive and Resistant Staphylococcus aureus Clinical Isolates Reveals Key Efflux
Shoaib Ashraf1,2,3, Débora Parrine4,5, Muhammad Bilal1
1Department of Animal Sciences, McGill University, Sainte-Anne-de-Bellevue, Quebec, QC H9X 3V9, Canada.
Abstract:
Ivermectin (IVM) is a versatile drug used against many microorganisms. Staphylococcus aureus is one of the most devastating microorganisms. IVM sensitive and resistant S. aureus strains were recently reported. However, the underlying molecular mechanisms of resistance are unknown. Clinical isolates of S. aureus were used for determination of the sensitivities against IVM by growth curve analysis and time-kill kinetics. Then, proteomic, and biochemical approaches were applied to investigate the possible mechanisms of resistance. Proteomic results showed a total of 1849 proteins in the dataset for both strains, 425 unique proteins in strain O9 (IVM sensitive), and 354 unique proteins in strain O20 (IVM resistant). Eight proteins with transport functions were differentially expressed in the IVM resistant strain. Among them, three efflux pumps (mepA, emrB, and swrC) were confirmed by qPCR. The IVM resistant S. aureus may overexpress these proteins as a key resistance determinant. Further experiments are required to confirm the exact mechanistic relationship. Nevertheless, the possibility of blocking these transporters to reverse or delay the onset of resistance and reduce selection pressure is potentially appealing.
Insights
Ivermectin resistance in Staphylococcus aureus is linked to increased expression of efflux pump proteins. Targeting these transporters may help overcome or delay resistance development.
Area of Science:
- Microbiology
- Molecular Biology
- Pharmacology
Background:
- Ivermectin (IVM) is a broad-spectrum antiparasitic and antimicrobial agent.
- Emergence of IVM-resistant Staphylococcus aureus strains necessitates understanding resistance mechanisms.
- The molecular basis for IVM resistance in S. aureus remains largely unknown.
Purpose of the Study:
- To investigate the molecular mechanisms underlying ivermectin resistance in Staphylococcus aureus.
- To identify potential protein targets involved in IVM resistance.
Main Methods:
- Phenotypic characterization of IVM sensitivity using growth curve analysis and time-kill kinetics.
- Proteomic analysis to compare protein expression profiles between sensitive and resistant strains.
- Quantitative PCR (qPCR) to validate differential expression of specific genes.
Main Results:
- Proteomic analysis identified differential expression of 8 proteins with transport functions in the IVM-resistant strain.
- Three efflux pump genes (mepA, emrB, swrC) were confirmed to be overexpressed in the resistant strain.
- Overexpression of these efflux pumps is a potential key determinant of IVM resistance in S. aureus.
Conclusions:
- The study suggests that overexpression of specific efflux pumps contributes to ivermectin resistance in S. aureus.
- Blocking these transporters could be a strategy to reverse or delay resistance and reduce selection pressure.
- Further research is needed to elucidate the precise mechanistic role of these transporters in IVM resistance.
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