Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections

Abstract

Antibiotic-resistant bacterial infections arising from acquired resistance and/or through biofilm formation necessitate the development of innovative 'outside of the box' therapeutics. Nanomaterial-based therapies are promising tools to combat bacterial infections that are difficult to treat, featuring the capacity to evade existing mechanisms associated with acquired drug resistance. In addition, the unique size and physical properties of nanomaterials give them the capability to target biofilms, overcoming recalcitrant infections. In this Review, we highlight the general mechanisms by which nanomaterials can be used to target bacterial infections associated with acquired antibiotic resistance and biofilms. We emphasize design elements and properties of nanomaterials that can be engineered to enhance potency. Lastly, we present recent progress and remaining challenges for widespread clinical implementation of nanomaterials as antimicrobial therapeutics.

Figure 1.. Nano versus micro – size comparison between nanomaterials and bacteria.

Bacteria typically have diameters ranging from 0.2 to 10 μm. Varying nanoparticle materials and preparation methods provide a wide range of particle sizes (2–500 nm) that facilitate maximal contact and strong interactions with bacterial membranes. Nanomaterials may display a variety of bactericidal mechanisms: I| Membrane disruption. Electrostatic interactions of NPs with the negatively charged groups present on bacterial surfaces results in membrane damage and cytoplasmic leakage. II| Intracellular damage. NPs can bind various bacterial components, such as ribosomes, proteins and/or DNA, interrupting their function. III| ROS. NPs with catalytic activities increase production of reactive oxygen species, such as hydroxyl radicals and superoxides, causing oxidative cellular stress. IV| Delivery. Nanomaterials can be used for delivery of therapeutic agents; some nanomaterials readily enter bacterial cells through membrane fusion, facilitating delivery of their cargo.

Figure 2.. Examples of nanomaterial-based strategies used to combat bacterial infections.

a-b| Planktonic bacterial infections. c-d| Intracellular infections. e-f| Biofilm infections. a| Structurally engineered AMPs, SNAPPs, exhibited promising antimicrobial activity in vitro and in vivo. SNAPPs interacts with the outer membrane, peptidoglycan and cytoplasmic membrane layers of bacteria through electrostatic interactions, ultimately leading to cell lysis. b| Intratracheal administration of antimicrobial esculentin-1a formulated to be delivered to the lungs using PLGA NPs reduced P. aeruginosa lung infection in a mouse model. c| Histidine-aptamer-conjugated gold nanoparticles loaded with His-tagged AMPs were effective for treatment of Salmonella enterica-infected mammalian cells. d| Gentamicin-loaded mesoporous silica nanoparticles with a bacterial toxin-responsive lipid bilayer surface shell and bacteria-targeting peptide UBI_29–41, allowed targeted release of antibiotic for killing of intracellular S. aureus. e| A carboxymethyl-dextran-coated iron oxide nanoparticle, ferumoxytol, catalyzed ROS production of H₂O₂ in a pH-dependent manner as a treatment against oral biofilms. f| Dextran (green) and poly(AMPTMA-co-BMA) (light blue) form a micelle with a bactericidal core and non-fouling dextran shell used to treat wound biofilms. Electrostatic interaction of the NPs with the biofilm weakens bacterial attachment while gradually dispersing EPS matrix. Image in part a reproduced, with permission, from REF © (2016) Macmillan Publishers Limited, part of Springer Nature. Image in part b reproduced, with permission, from REF © (2019) American Chemical Society. Image in part c reproduced, with permission, from REF © (2016) Elsevier Ltd. Image in parts d and f reproduced, with permission, from REF and , respectively © (2018) American Chemical Society. Image in part e reproduced, with permission, from REF. © (2018) Nature Communications. All rights reserved.

Figure 3.. Eradicating biofilms using NPs.

Biofilms are comprised of cells with phenotypic heterogeneity embedded across the 3D-matrix of their self-secreted EPS. The ability of NPs to penetrate throughout the matrix allows them to a| interact with cells entrenched within the EPS and/or b| initiate disruptive interactions with the matrix that weaken physicochemical interactions responsible for keeping the 3D structure of biofilms intact. NPs can then either exert their inherent antimicrobial action or deliver therapeutic agents, such as antibiotics or essential oils, to kill the bacteria within the biofilms. NPs can alternatively deliver EPS-degrading molecules that promote dispersion of biofilms, facilitating their disruption.