Available online 28 August 2022, 106666

Pre-treatment of methicillin resistant Staphylococcus aureus to daptomycin causes a synergistic effect on human neutrophil's-mediated biofilm damage.

Human monocytes exposed to either daptomycin or methicillin resistant Staphylococcus aureus biofilms respond with an upregulation of inflammatory cytokines.

Daptomycin may condition monocytes towards an inflammatory response, possibly controlling biofilm-associated pathogenicity. Such activity may benefit the optimal use of this antibiotic especially among immunocompromised patients.

: Daptomycin (DAP) is indicated for difficult-to-treat Gram-positive infections, especially those caused by methicillin-resistant S. aureus (MRSA). Exposure of S. aureus to sub-inhibitory concentrations (sub-MICs) of antibiotics have been shown to alter cell morphology or biofilm formation.

: To investigate the influence of DAP biofilm sub-MICs on the damage caused by human polymorphonuclear neutrophils (PMNs) against MRSA biofilms and the potential immunomodulatory activity of DAP on human monocytes (MNCs) exposed to MRSA biofilms.

: DAP activity against biofilms and the impact of DAP on the PMNs-induced biofilm damage were evaluated by the XTT reduction assay, whereas pathogen recognition, signal transduction and cytokine modulation of DAP on MNCs in response to MRSA biofilms were assessed by RT-PCR and ELISA methodology.

: The MIC50 of DAP to MRSA biofilms was 16 to 32 mg/L. Pre-treatment of MRSA to 1, 2 or 4 mg/L DAP caused a synergistic effect on PMN-mediated biofilm damage, being dependent on the effector-to-target ratio. MNCs responded to MRSA biofilms and DAP through Toll like receptor 2 (TLR2) upregulation and increased NLRP3 inflammasome production. DAP caused 2.5-fold greater TLR2 mRNA levels than those caused by MRSA biofilms. A predominantly inflammatory response was induced by either component, causing the release of significantly increased IFN-γ, TNF-α, IL-8 and IL-6 levels by MNCs exposed to the combination treatment. MRSA biofilms alone or combined with DAP caused low amounts of IL-10 production, but increased IL-1β levels.

: DAP may condition MNCs towards an inflammatory response through TLR2 engagement and NLRP3 inflammasome activation, possibly controlling biofilm-associated pathogenicity.

daptomycin

Staphylococcus aureus biofilms

immunomodulation

immune recognition

cytokines

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