Biomaterial-based delivery of antimicrobial therapies for the treatment of bacterial infections

Abstract

The rise in antibiotic-resistant bacteria, including strains that are resistant to last-resort antibiotics, and the limited ability of antibiotics to eradicate biofilms, have necessitated the development of alternative antibacterial therapeutics. Antibacterial biomaterials, such as polycationic polymers, and biomaterial-assisted delivery of non-antibiotic therapeutics, such as bacteriophages, antimicrobial peptides and antimicrobial enzymes, have improved our ability to treat antibiotic-resistant and recurring infections. Biomaterials not only allow targeted delivery of multiple agents, but also sustained release at the infection site, thereby reducing potential systemic adverse effects. In this Review, we discuss biomaterial-based non-antibiotic antibacterial therapies for the treatment of community- and hospital-acquired infectious diseases, with a focus in in vivo results. We highlight the translational potential of different biomaterial-based strategies, and provide a perspective on the challenges associated with their clinical translation. Finally, we discuss the future scope of biomaterial-assisted antibacterial therapies.

Web summary: The development of antibiotic tolerance and resistance has demanded the search for alternative antibacterial therapies. This Review discusses antibacterial biomaterials and biomaterial-assisted delivery of non-antibiotic therapeutics for the treatment of bacterial infectious diseases, with a focus on clinical translation.

Figure 1.. Biomaterial-based antibacterial therapies.

A) Challenges in the treatment of bacterial biofilm infections. Limited penetration of antibiotics into the biofilm owing to the presence of extracellular polymeric substances (EPS) limits the local concentration of the antibiotic at the site of infection, leading to inefficient mitigation of infection and to the development of tolerance and resistance. B) Optimal properties of biomaterial-assisted antibacterial therapies to treat challenging bacterial infections. The biomaterial can protect antibacterial agents from proteolytic enzymes in the body and facilitate the simultaneous delivery of multiple agents to treat infections, modulate immune responses and restore physiological conditions.

Figure 2.. Proposed mechanism-of-action of different non-antibiotic antibacterial agents.

Cationic antimicrobial peptides and polymers can cause bacterial cell lysis through membrane perturbation. Proposed models for the underlying mechanism are the barrel stave model, the toroidal pore model and the carpet model. Alternatively, some peptides are proposed to cause bacterial death through membrane translocation followed by disruption of natural processes, such as DNA and RNA synthesis, protein synthesis and protein folding, which leads to cell death. Lysostaphin binds to the peptidoglycan layer of the bacterial cell wall in Gram-positive bacteria, such as S. aureus, and cleaves the pentaglycin bridges, leading to lysis and cell death. AMP, antimicrobial peptides. Adapted from ref. ^,

Figure 3.. Nano- and microparticle-based antibacterial therapies.

A) Poly(lactic-co-glycolic acid) porous microparticles can be used for bacteriophage delivery and can be formulated as dry powder. B) Chitosan-peptide composite nanoparticles prolong the retention time at the site of infection. C) Magnetic nanorobots enable biofilm degradation. EPS, extracellular polymeric substances; PEG, poly(ethylene glycol). Reproduced from ref.^,,

Hydrogel-based antibacterial therapies.

A) A pH-switchable hydrogel can be assembled by an antimicrobial peptide (AMP) with alternating hydrophobic and hydrophilic amino acid sequences, and opposite charges at each end. At neutral pH, the AMP self-assembles into a supramolecular hydrogel matrix by non-covalent electrostatic interactions and hydrogen bonding. At low pH (pH = 5.5), the hydrogel disassembles and releases the AMP. B) Schematic of a 4-arm polyethylene glycol (4-arm PEG) hydrogel that can be used for the delivery of lysostaphin. A 10 kDa 4-arm PEG macromer with maleimide functional groups can be cross-linked with a bi-thiol substituted degradable cross-linker and thiol-bearing, collagen-mimetic peptides (GFOGER). Lysostaphin is physically encapsulated within the hydrogel. Reproduced from ref.^,