Beyond the Wild MRSA: Genetic Features and Phylogenomic Review of mecC -Mediated Methicillin Resistance in Non- aureus Staphylococci and Mammaliicocci.

Methicillin resistance, mediated by the mecA gene in staphylococci and mammaliicocci, has caused tremendous setbacks in the use of antibiotics in human and veterinary medicine due to its high potential of presenting the multidrug resistance (MDR) phenotype. Three other mec analogs exist, of which the mecC has evolutionary been associated with methicillin-resistant Staphylococcus aureus (MRSA) in wild animals, thus loosely referred to as the wild MRSA. In this study, we present an epidemiological review and genomic analysis of non- aureus staphylococci and mammaliicocci that carry the mecC -mediated methicillin resistance trait and determine whether this trait has any relevant link with the One Health niches. All previous studies (2007 till 2023) that described the mecC gene in non- aureus staphylococci and mammaliicocci were obtained from bibliometric databases, reviewed, and systematically analyzed to obtain the antimicrobial resistance (AMR) and virulence determinants, mobilome, and other genetic contents. Moreover, core genome single-nucleotide polymorphism analysis was used to assess the relatedness of these strains. Of the 533 articles analyzed, only 16 studies (on livestock, environmental samples, milk bulk tanks, and wild animals) were eligible for inclusion, of which 17 genomes from 6 studies were used for various in silico genetic analyses. Findings from this systematic review show that all mecC -carrying non- aureus staphylococci were resistant to only beta-lactam antibiotics and associated with the classical SCC mec XI of S. aureus LGA251 . Similarly, two studies on wild animals reported mecC -carrying Mammaliicoccus stepanovicii associated with SCC mec XI. Nevertheless, most of the mecC -carrying Mammaliicoccus species presented an MDR phenotype (including linezolid) and carried the SCC mec - mecC hybrid associated with mecA. The phylogenetic analysis of the 17 genomes revealed close relatedness (<20 SNPs) and potential transmission of M. sciuri and M. lentus strains in livestock farms in Algeria, Tunisia, and Brazil. Furthermore, closely related M. sciuri strains from Austria, Brazil, and Tunisia (<40 SNPs) were identified. This systematic review enhances our comprehension of the epidemiology and genetic organization of mecC within the non- aureus staphylococci and mammaliicocci. It could be hypothesized that the mecC -carrying non- aureus staphylococci are evolutionarily related to the wild MRSA- mecC . The potential implications of clonal development of a lineage of mecA/mecC carrying strains across multiple dairy farms in a vast geographical region with the dissemination of MDR phenotype is envisaged. It was observed that most mecC -carrying non- aureus staphylococci and mammaliicocci were reported in mastitis cases. Therefore, veterinarians and veterinary microbiology laboratories must remain vigilant regarding the potential existence of mecA/mecC strains originating from mastitis as a potential niche for this resistance trait.