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

Abstract

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.

Potential combinations of endocannabinoid/endocannabinoid-like compounds and antibiotics against methicillin-resistant Staphylococcus aureus

“…Another study demonstrated that the amphiphilic biosurfactant sophorolipid interacts positively with TET against S. aureus via alteration of bacterial membrane integrity, which facilitates penetration of the antibiotic [40]. Furthermore, the amphiphilic nanocarrier C1-PNC compromises the MRSA cell membrane; combined with GEN, this allows elevated cellular uptake of the antibiotic, which in turn leads to elimination of bacterial cells [41]. Our previous results demonstrated that single AEA or AraS, at sub-killing concentrations, were able to destabilize the cytoplasmic membrane of MRSA [22].…”

Novel Thiadiazole-Based Molecules as Promising Inhibitors of Black Fungi and Pathogenic Bacteria: In Vitro Antimicrobial Evaluation and Molecular Docking Studies

“…Ciprofloxacin, which is considered one of the most popular antibiotics, was reported to be beneficial against various types of Gram-positive and Gram-negative species [ 40 ]. Likewise, it has potent antibacterial properties against E. coli , P. aeruginosa , S. aureus , and Enterococcus faecium [ 41 ].…”

Discovery of 4,6‐bis(2‐((E)‐benzylidene)hydrazinyl)pyrimidin‐2‐Amine with Antibiotic Activity

“…Our critical reliance on antibiotics has engendered government initiatives and global strategies to rejuvenate the antibiotic pipeline, such as the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB‐X) initiative and “The 10×20 Initiative” seek to combat this crisis and has the ambitious target of ten new antibacterial drugs by 2020 . Whilst these ambitious targets have stimulated a resurgence in antibacterial research at the academic level, this research has failed to translate into new antibiotics with novel mechanisms of action . Of particular concern is the lack of efficacious compounds which treat Gram‐negative bacteria, owing to the poor drug penetration of the outer membrane and the efficient efflux systems widespread within this group of microbes, making these pathogens extremely challenging to treat .…”

“…Both the Infectious Diseases Society of America and the European Centre for Disease Control have announced that only a handful of potential drugs which target Gram‐negative bacteria in clinical trials offer significant benefits over current clinically used antibiotics . Clearly there is a pressing need to develop new antibiotic classes, especially those with lower inherent resistance susceptibility …”