New Weapons to Fight against Staphylococcus aureus Skin Infections

Abstract

The treatment of Staphylococcus aureus skin and soft tissue infections faces several challenges, such as the increased incidence of antibiotic-resistant strains and the fact that the antibiotics available to treat methicillin-resistant S. aureus present low bioavailability, are not easily metabolized, and cause severe secondary effects. Moreover, besides the susceptibility pattern of the S. aureus isolates detected in vitro, during patient treatment, the antibiotics may never encounter the bacteria because S. aureus hides within biofilms or inside eukaryotic cells. In addition, vascular compromise as well as other comorbidities of the patient may impede proper arrival to the skin when the antibiotic is given parenterally. In this manuscript, we revise some of the more promising strategies to improve antibiotic sensitivity, bioavailability, and delivery, including the combination of antibiotics with bactericidal nanomaterials, chemical inhibitors, antisense oligonucleotides, and lytic enzymes, among others. In addition, alternative non-antibiotic-based experimental therapies, including the delivery of antimicrobial peptides, bioactive glass nanoparticles or nanocrystalline cellulose, phototherapies, and hyperthermia, are also reviewed.

Keywords: Staphylococcus aureus; antibiotic resistance; drug bioavailability; drug delivery; experimental therapies; skin infections.

Figure 1

Action of nanoparticles on the bacterial membrane. Metal nanoparticles (NPs) release positively charged ions that alter membrane function, which leads to increased intracellular ROS levels and eventually cause bacterial destruction. NPs can be conjugated to different drugs (including antibiotics) to facilitate their delivery and may have a synergistic effect on bacterial killing.

Figure 2

Antisense technologies to restore sensitivity to β-lactam antibiotics. Antisense oligonucleotides coupled to gold nanoparticles (AuNPs) delivered using liposomal nanocarriers can block gene expression of mecA or mecR1 to restore sensitivity to methicillin.

Figure 3

Nanocarriers used to improve drug delivery. Solid dispersions: these are formed by two or more solid components, generally a hydrophilic polymeric matrix (such as PVP or PEG) and a hydrophobic drug. Cyclodextrins: the cylindrical shape allows the drug to be kept within the hydrophobic interior, while the outer surface is hydrophilic and soluble in aqueous solutions. Lipid-based carriers: Micelles, polymeric micelles, and nano- or microemulsions are composed of a monolayer (one or more surfactants) and a hydrophobic core and serve to carry hydrophobic drugs. Vesicles have a hydrophilic core and, according to their composition, can be classified as liposomes (phospholipids), niosomes (non-ionic surfactants with or without cholesterol) or polymer-hybrid vesicles (liposomes or niosomes coated with polymers) and serve to carry hydrophobic or hydrophilic drugs.

Figure 4

Trojan-horse-like strategy. Siderophores or sugar-crafted cyclodextrins can facilitate antibiotic delivery through the uptake by their specific siderophore or sugar transporters in the cytoplasmic membrane and subsequent release of the antibiotic in the bacterial cytoplasm.

Figure 5

Electromagnetic spectrum. The region of the spectrum used for phototherapy is highlighted.

Figure 6

S. aureus-targeted magnetic nanoparticle hyperthermia. Magnetite (Fe₃O₄) coated with streptavidin and a biotinylated anti-protein A (SpA) antibody (anti-SA) binds to the S. aureus cell wall, and the alternating magnetic field (AMF) can induce thermal inactivation.