Methicillin resistant Staphylococcus aureus (MRSA) is considered as the most frequent cause of bacteraemia worldwide1, 2. Protection against MRSA infection is challenging and requires both innate and adaptive immune effector mechanisms. Being at the interface between innate and adaptive immune responses, dendritic cells (DC) are thus central to the immune protection against MRSA. We have previously shown that distinct and paired clinical isolates of MRSA have differential capacity to induce DC activation. Clinical isolates resistant to the last‐line antibiotic Daptomycin (DapR) induced a compromised DC activation compared with the Daptomycin sensitive (DapS) paired isolate3. In the present study, we explore the molecular mechanisms by which DapR MRSA strains impede DC activation. We investigated the role of Toll-Like Receptor 2(TLR2) and intracellular PRRs cGAS and STING in the response of DC to DapS and DapR paired clinical isolates of MRSA. In this study, blocking of TLR2 demonstrated a partial, similar reduction in the production of IL-6 for both DapS and DapR clinical isolates, indicating the role of TLR2 in the initial recognition of cell wall components. We further found that acquisition of daptomycin resistance in MRSA inhibits the ability of DC to recognise the DapR MRSA via the cGAS/STING signalling pathway. DapR MRSA is not actively inhibiting this pathway but rather, its DNA fails to be recognised. Our work, thus provides important insights for the mechanism of differential recognition of clinical isolates of DapS and DapR MRSA by DC, providing insight into how acquisition of antibiotic resistance can have downstream consequences on innate recognition by the immune system.