Engineered Polymer Nanoparticles with Unprecedented Antimicrobial Efficacy and Therapeutic Indices against Multidrug-Resistant Bacteria and Biofilms

Abstract

The rapid emergence of antibiotic-resistant bacterial "superbugs" with concomitant treatment failure and high mortality rates presents a severe threat to global health. The superbug risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that render them refractory to available treatments. We hypothesized that efficient antimicrobial agents could be generated through careful engineering of hydrophobic and cationic domains in a synthetic semirigid polymer scaffold, mirroring and amplifying attributes of antimicrobial peptides. We report the creation of polymeric nanoparticles with highly efficient antimicrobial properties. These nanoparticles eradicate biofilms with low toxicity to mammalian cells and feature unprecedented therapeutic indices against red blood cells. Most notably, bacterial resistance toward these nanoparticles was not observed after 20 serial passages, in stark contrast to clinically relevant antibiotics where significant resistance occurred after only a few passages.

Antibiotic‐Free Antibacterial Strategies Enabled by Nanomaterials: Progress and Perspectives

“…Copyright 2018, American Chemical Society. j) Reproduced with permission . Copyright 2018, American Chemical Society.…”

“…Compared to hyaluronic acid‐modified particles with negatively charged surfaces, nanoparticles coated with aminocellulose with a positively charged surface exhibited enhanced interactions with bacterial membranes, resulting in enhanced cell wall damage and bactericidal activity (Figure i) 32d. Recently, hydrophobic and cationic alkyl chains with tunable chain lengths have been grafted onto nanomaterial surfaces to enhance bacterial membrane disruption (Figure j) . Increased hydrophobicity from longer alkyl chains contributed to a lower minimum inhibitory concentration (MIC).…”

“…Increased hydrophobicity from longer alkyl chains contributed to a lower minimum inhibitory concentration (MIC). No significant bacterial resistance was observed, while obvious resistance to clinical antibiotics appeared after a few passages …”

“…Nanomaterials have a large variety of compositions and thus offer a number of unique advantages. First, the physiochemical properties of nanomaterials, such as size, surface chemistry, and shape, can be precisely controlled, leading to functional materials with intrinsic antibacterial activity through cell membrane damage or nutrient starvation, light‐assisted antibacterial activity, and immunomodulation . Second, nanomaterials can act as delivery vehicles to facilitate the permeability, controlled release, and targeted bacterial uptake of natural compounds and improve their stability for bacterial inhibition or as adjuvants in vaccine formulations, thus improving the potency with reduced dosage .…”

Biodegradable Antibacterial Polymeric Nanosystems: A New Hope to Cope with Multidrug‐Resistant Bacteria

“…Although antibiotic‐containing nanosystems significantly enhance antibacterial efficacy and slow down the emergences of multidrug resistant superbugs, the development of new materials with intrinsic antibacterial activities is still in urgent demand. Over the recent decades, the developments of polymers with intrinsic antimicrobial moieties, such as quaternary ammonium (QA) groups, phosphonium groups, AMPs and their synthetic mimics, have attracted striking attention in the field of biomaterials. In a pioneer work, a series of biodegradable triblock copolymers were synthesized via ring‐opening polymerization, containing two hydrophobic poly(trimethylene carbonate) (PTMC) blocks to form the core of micelles, and quaternized bactericidal blocks to form the shell of the micelles, as shown in Figure .…”