PLGA Nanoparticles Formulations Loaded With Antibiotics Induce Sustained and Controlled Antibiotics Release for Prolonged Antibacterial Action Against MRSA, and Pseudomonas aeruginosa FRD1.

The purpose of the present study was to create resorbable nanoparticles (NPs) using poly(lactic-co-glycolic acid) (PLGA) to develop novel antibacterial therapeutics for the treatment of chronic wound infections that are susceptible to recurrent infections. By first performing a release study, it was possible to predict the behavior of the different PLGA NP formulations and assess the efficacy of the nanocomposite drug delivery system. These PLGA NP formulations consisted of varying ratios of PLGA without polyvinyl alcohol (PVA) and PLGA with PVA (PLGA-PVA) (i.e., 25:75[PLGA25], 50:50[PLGA50], and 75:25[PLGA75]). Then, different antibiotics (i.e., ciprofloxacin and gentamicin) were incorporated into the PLGA NP formulations to test the antibacterial efficacy of these antimicrobial NPs against different pathogens (i.e., methicillin-resistant Staphylococcus aureus USA300 [MRSA], Pseudomonas aeruginosa FRD1, and Acinetobacter baumannii BAA1605). Of particular interest was testing against the MRSA strain USA300 and the P. aeruginosa strain FRD1. This was possible by measuring the zone of inhibition. A 3-day period was used to monitor the antibacterial efficacy of the different PLGA NP formulations (i.e., PLGA25, PLGA50, and a 1:1 combination of PLGA25:PLGA50) against A. baumannii BAA1605, MRSA, and P aeruginosa FRD1. Throughout the study, A. baumannii was a negative control and was resistant to all the PLGA NP formulations loaded with ciprofloxacin and gentamicin. At the end of the 3-day period, the PLGA and PLGA50 ciprofloxacin-loaded formulations produced zones of inhibition of 27 mm and 23 mm, respectively, against P. aeruginosa FRD1. This indicated that P. aeruginosa FRD1 was susceptible to both formulations. The mixed formulations with equal parts PLGA25:PLGA50 loaded with ciprofloxacin produced a zone of inhibition (i.e., 25 mm). This again indicated that P. aeruginosa FRD1 was susceptible to ciprofloxacin. The formulations tested against MRSA showed that only gentamicin-loaded formulations produced intermediate results, and that ciprofloxacin-loaded formulations were ineffective. The PLGA25 and the PLGA50 NP formulations loaded with gentamicin both produced zones of inhibition of 13 mm. This indicated that MRSA was intermediate to both the formulations. The PLGA25:PLGA50 loaded with gentamicin produced a zone of inhibition of 14 mm, which again showed that MRSA was intermediate to this formulation. Overall, these PLGA NP formulations showed the sustained antibacterial potential of a burst release, followed by a sustained release of antibiotics from antibiotics loaded PLGA NPs in a controlled manner. In the future, this can help prevent the emergence of recurrent infections in the treatment of chronic wounds and reduce the number of medical dressing changes.

Antimicrobial peptide-conjugated phage-mimicking nanoparticles exhibit potent bactericidal action against Streptococcus pyogenes in murine wound infection models.

Streptococcus pyogenes is a causative agent for strep throat, impetigo, and more invasive diseases. The main reason for the treatment failure of streptococcal infections is increased antibiotic resistance. In recent years, infectious diseases caused by pyogenic streptococci resistant to multiple antibiotics have been rising with a significant impact on public health and the veterinary industry. The development of antibiotic resistance and the resulting emergence of multidrug-resistant bacteria have become primary threats to the public health system, commonly leading to nosocomial infections. Many researchers have turned their focus to developing alternative classes of antibacterial agent based on various nanomaterials. We have developed an antibiotic-free nanoparticle system inspired by naturally occurring bacteriophages to fight antibiotic-resistant bacteria. Our phage-mimicking nanoparticles (PhaNPs) display structural mimicry of protein-turret distribution on the head structure of bacteriophages. By mimicking phages, we can take advantage of their evolutionary constant shape and high antibacterial activity while avoiding the immune reactions of the human body experienced by biologically derived phages. We describe the synthesis of hierarchically arranged core-shell nanoparticles, with a silica core conjugated with silver-coated gold nanospheres to which we have chemisorbed the synthetic antimicrobial peptide Syn-71 on the PhaNPs surface, and increased the rapidity of the antibacterial activity of the nanoparticles (PhaNP@Syn71). The antibacterial effect of the PhaNP@Syn71 was tested in vitro and in vivo in mouse wound infection models. In vitro, results showed a dose-dependent complete inhibition of bacterial growth (>99.99%). Cytocompatibility testing on HaCaT human skin keratinocytes showed minimal cytotoxicity of PhaNP@Syn71, being comparable to the vehicle cytotoxicity levels even at higher concentrations, thus proving that our design is biocompatible with human cells. There was a minimum cutoff dosage above which there was no evolution of resistance after prolonged exposure to sub-MIC dosages of PhaNP@Syn71. Application of PhaNP@Syn71 to a mouse wound infection model exhibited high biocompatibility in vivo while showing immediate stabilization of the wound size, and infection free wound healing. Our results suggest the robust utility of antimicrobial peptide-conjugated phage-mimicking nanoparticles as a highly effective antibacterial system that can combat bacterial infections consistently while avoiding the emergence of resistant bacterial strains.