Widespread emergence of <i>Staphylococcus aureus</i> with variant FarR regulators and enhanced resistance to antimicrobial fatty acids within clonal complex CC5, CC8, and CC97 strains from human and bovine hosts

The FarER efflux pump and regulator confer inducible resistance of <i>Staphylococcus aureus</i> 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 <i>farR</i> through <i>in vitro</i> selection for increased resistance to linoleic acid, leading to recovery of FarR^H121Y that promoted enhanced expression of <i>farE</i>. Here, we report on the widespread emergence of increased resistance to linoleic acid across the phylogenetic spectrum of <i>S. aureus</i> through mechanisms that are both dependent and independent of <i>farER</i>. In this latter group, sequence type ST228 healthcare-associated methicillin-resistant <i>S. aureus</i> has FarR^A14P that is defective in DNA binding and cannot induce <i>farE</i> expression, and yet these strains exhibit enhanced resistance to linoleic acid. In the former group, we note the polyphyletic emergence of FarR^G166D in ST5 community-acquired MRSA (CA-MRSA), adding to previously noted variants FarR^C116Y and FarR^E160G in ST5 MRSA. We also observe FarR^H121Y and FarR^G166D in ST97 methicillin-susceptible <i>S. aureus</i> from bovine hosts, together with polyphyletic emergence of FarR^C116Y. Last, we note the emergence of FarR^H121Y in the USA300 lineage of ST8 CA-MRSA from the UK, in association with an SCC<i>mec</i> 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 <i>S. aureus</i> strains from both human and bovine hosts, with enhanced resistance to unsaturated free fatty acids that comprise an important chemical component of innate immunity.IMPORTANCE<i>Staphylococcus aureus</i> 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 <i>S. aureus</i> 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 <i>S. aureus</i> 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, <i>S. aureus</i> 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 <i>S. aureus</i> to evolve in response to antimicrobial threats.