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 susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC could render 8 × and 6 × reduction of the minimum biofilm eradication concentration (MBEC90) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in case of gentamicin, C1-PNC promoted enhanced cellular uptake of the antibiotic, while 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 non-toxic to cultured HEK 293 cells. It is conceived that the non-toxic amphiphile-loaded nanomaterial holds considerable prospect as an adjuvant for antibiotic-mediated alleviation of MRSA biofilm.