Balancing the Virulence and Antimicrobial Resistance in VISA DAP-R CA-MRSA Superbug

Background: Methicillin-resistant Staphylococcus aureus (MRSA) with intermediate resistance to Vancomycin (VISA) is reported worldwide. These strains frequently emerge among hospital-associated (HA)-MRSA and rarely within community-acquired (CA)-MRSA. Here, the genomic and transcriptomic adaptations distinguishing VISA daptomycin resistant (DAP-R) CA-MRSA, which emerged in a hospitalized patient under glycopeptide treatment, were explored. Methods: Whole-genome sequencing, RNA-Seq and bioinformatics were carried out. Results: Our CA-MRSA clustered in the USA400 lineage showing additional antimicrobial resistance (AMR) versus DAP and glycopeptides. Resistomics revealed adaptations related to glycopeptide, daptomycin and rifampin resistance (mprF nsSNPS and overexpression of glycopeptide and daptomycin-resistance related genes). Similar changes were detected in virulence traits (agrA HI-nsSNPs and toxin gene underexpression), in which a decrease was observed despite the abundance of virulence-related genes. Our results predicted a balance in adaptations, decreasing the virulence and biological costs to support the co-occurrence of extensive AMR in a hypervirulent genomic background. Conclusion: Our data show that VISA DAP-R CA-MRSA shifts the potential hypervirulent behavior of CA-MRSA towards the acquisition and maintenance of extensive AMR, by a decrease in virulence and biological costs mediated by a "compensatory modulatory mutation" silencing the Agr quorum-sensing cascade.