Proteomic Comparison of Ivermectin Sensitive and Resistant Staphylococcus aureus Clinical Isolates Reveals Key Efflux Pumps as Possible Resistance Determinants

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.