Amphiphilic Cargo-Loaded Nanocarrier Enhances Antibiotic Uptake and Perturbs Efflux: Effective Synergy for Mitigation of Methicillin-Resistant Staphylococcus aureus.

A pyridinium-amphiphile-loaded poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC was found to render 8- and 6-fold decreases in the minimum biofilm eradication concentration (MBEC ) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in the case of gentamicin, C1-PNC promotes enhanced cellular uptake of the antibiotic, whereas the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin, leading to effective killing of MRSA cells. Interestingly, the combinatorial dosing regimen of C1-PNC and the antibiotics was nontoxic to cultured HEK293 cells. This nontoxic amphiphile-loaded nanomaterial holds considerable promise as an adjuvant for antibiotic-mediated alleviation of MRSA biofilms.