Abstract

The FarER efflux pump and regulator confer inducible resistance of Staphylococcus aureus to linoleic acid, an unsaturated antimicrobial fatty acid that comprises a chemical component of innate immunity at sites of colonization and infection. We previously discovered farR through in vitro selection for increased resistance to linoleic acid, leading to recovery of FarRH121Y that promoted enhanced expression of farE. Here, we report on the widespread emergence of increased resistance to linoleic acid across the phylogenetic spectrum of S. aureus through mechanisms that are both dependent and independent of farER. In this latter group, sequence type ST228 healthcare-associated methicillin-resistant S. aureus has FarRA14P that is defective in DNA binding and cannot induce farE expression, and yet these strains exhibit enhanced resistance to linoleic acid. In the former group, we note the polyphyletic emergence of FarRG166D in ST5 community-acquired MRSA (CA-MRSA), adding to previously noted variants FarRC116Y and FarRE160G in ST5 MRSA. We also observe FarRH121Y and FarRG166D in ST97 methicillin-susceptible S. aureus from bovine hosts, together with polyphyletic emergence of FarRC116Y. Last, we note the emergence of FarRH121Y in the USA300 lineage of ST8 CA-MRSA from the UK, in association with an SCCmec VI element that encodes resistance to fusidic acid, a topical antimicrobial used to treat superficial skin infections. Our data support the widespread emergence and dissemination of S. aureus strains from both human and bovine hosts, with enhanced resistance to unsaturated free fatty acids that comprise an important chemical component of innate immunity.IMPORTANCEStaphylococcus aureus is a priority pathogen for the World Health Organization due to its association with human morbidity, mortality, and acquisition of multiple drug resistance. In addition to acquiring specific antimicrobial resistance genes, it is also widely documented that S. aureus can evolve through accumulation of genetic polymorphisms that confer reduced susceptibility to some antibiotics such as daptomycin and vancomycin. In this study, we report on the widespread emergence of S. aureus strains with sufficiency for increased resistance to antimicrobial fatty acids through polymorphisms in the regulator of an efflux pump. This is an indication that, in addition to evolution in response to antibiotics that are used to treat infections, S. aureus also exhibits the capacity to evolve in response to antimicrobial unsaturated fatty acids that are important chemical components of innate immunity. These findings underscore the exceptional capacity of S. aureus to evolve in response to antimicrobial threats.