cGAS/STING sensing in dendritic cells discriminates between daptomycin sensitive and resistant Staphylococcus aureus clinical isolates.

Antimicrobial-resistant infections present significant threats to public health, predicted to cause 10 million fatalities annually by 2050. Of these infections, one of the most frequent is methicillin-resistant Staphylococcus aureus (MRSA). During therapeutic exposure to last-line antibiotics, including daptomycin, MRSA often acquires genetic mutations conferring resistance. Resistance is typically mediated through structural alterations to the bacterial cell wall and membrane, which we have previously shown, concomitantly impede the activation of responding dendritic cells (DCs). Here, we demonstrate how MRSA acquisition of daptomycin resistance impedes innate immune sensing by DC. We show that the acquisition of daptomycin resistance reduced phagocytosis by DC, and that it impaired the recognition of resistant isolates via the cytoplasmic cGAS/STING pathway, affecting the production of cyclic dinucleotides produced by both the host and the bacterium. Our research uncovers a mechanism by which antibiotic resistance mutations can simultaneously hinder the innate immune system's ability to recognize bacteria.