Abstract
Enterococcus faecalis (E. faecalis) biofilms are implicated in endocarditis, urinary tract infections, and biliary tract infections. Coupled with E. faecalis internalization into host cells, this opportunistic pathogen poses great challenges to conventional antibiotic therapy. The inability of ampicillin (Amp) to eradicate bacteria hidden in biofilms and intracellular niches greatly reduces its efficacy against complicated E. faecalis infections. To enhance the potency of Amp against different forms of E. faecalis infections, Amp was loaded into Lipid-Polymer hybrid Nanoparticles (LPNs), a highly efficient nano delivery platform consisting of a unique combination of DOTAP lipid shell and PLGA polymeric core. The antibacterial activity of these nanoparticles (Amp-LPNs) was investigated in a protozoa infection model, achieving a much higher multiplicity of infection (MOI) compared with studies using animal phagocytes. A significant reduction of total E. faecalis was observed in all groups receiving 250 μg/mL Amp-LPNs compared with groups receiving the same concentration of free Amp during three different interventions, simulating acute and chronic infections and prophylaxis. In early intervention, no viable E. faecalis was observed after 3 h LPNs treatment whereas free Amp did not clear E. faecalis after 24 h treatment. Amp-LPNs also greatly enhanced the antibacterial activity of Amp at late intervention and boosted the survival rate of protozoa approaching 400%, where no viable protozoa were identified in the free Amp groups at the 40 h postinfection treatment time point. Prophylactic effectiveness with Amp-LPNs at a concentration of 250 μg/mL was exhibited in both bacteria elimination and protozoa survival toward subsequent infections. Using protozoa as a surrogate model for animal phagocytes to study high MOI infections, this study suggests that LPN-formulated antibiotics hold the potential to significantly improve the therapeutic outcome in highly complicated bacterial infections.
Highlights
Enterococcus faecalis (E. faecalis) biofilms are implicated in endocarditis, urinary tract infections, and biliary tract infections
Using protozoa as a surrogate model for animal phagocytes to study high multiplicity of infection (MOI) infections, this study suggests that Lipid-Polymer hybrid Nanoparticles (LPNs)-formulated antibiotics hold the potential to significantly improve the therapeutic outcome in highly complicated bacterial infections
Being the second most common cause of infective endocarditis, E. faecalis infects the heart valves and forms biofilms (i.e., “vegetations”) mostly in people with cardiovascular conditions.3−5 It is seen in people with urinary catheters, colonizing and forming biofilms on the catheter surface.6−8 Conventionally, E. faecalis infections are treated with ampicillin (Amp) despite the fact that all enterococci have decreased susceptibility to penicillin and Amp intrinsically due to the production of low-affinity penicillin-binding proteins.9−11 In cases where the optimal treatment conditions for E. faecalis infections cannot be met, such as in biofilms and intracellular niches, antibiotic therapy fails and leads to intractable chronic infections
Summary
We fabricated an ampicillin encapsulated lipidpolymer hybrid nanoparticle system which hybridizes the properties of liposomal and polymeric systems. We demonstrated the utility of an E. faecalis and T. pyriformis coculture model as a surrogate phagocytic model to assess the anti-intracellular bacteria and antibiofilm activity of antibiotic-loaded LPNs. The results support the utility of this nanoantibiotic technology for the treatment of intracellular E. faecalis. It is evident that the LPN is capable of improving the therapeutic efficacy of Amp to combat E. faecalis in both early and late interventions, and provides significant prophylactic effectiveness for T. pyriformis cells. It is believed and expected that with further investigations into the physiochemical properties of antibiotic-loaded LPNs and a deeper understanding of the relationship between the host and invading pathogens, the LPN system can be endorsed with further enhancing antimicrobial effects toward different bacteria at different severities of infection
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