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The antibacterial efficacy and specificity of lytic bacteriophages (phages) make them promising therapeutics for treatment of multidrug-resistant bacterial infections. Restricted penetration of phages through the protective matrix of biofilms, however, may limit their efficacy against biofilm infections. Here, engineered polymers were used to generate noncovalent phage-polymer nanoassemblies (PPNs) that penetrate bacterial biofilms and kill resident bacteria. Phage K, active against multiple strains of Staphylococcus aureus , including methicillin-resistant S. aureus (MRSA), was assembled with cationic poly(oxanorbornene) polymers into PPNs. The PPNs retained phage infectivity, while demonstrating enhanced biofilm penetration and killing relative to free phages. PPNs achieved 3-log 10 bacterial reduction (∼99.9%) against MRSA biofilms in vitro. PPNs were then incorporated into Poloxamer 407 (P407) hydrogels and applied onto in vivo wound biofilms, demonstrating controlled and sustained release. Hydrogel-incorporated PPNs were effective in a murine MRSA wound biofilm model, showing a 1.5-log 10 reduction in bacterial load compared to a 0.5 log reduction with phage K in P407 hydrogel. Overall, this work showcases the therapeutic potential of phage K engineered with cationic polymers for treating wound biofilm infections.

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of Escherichia coli and Pseudomonas aeruginosa . This study highlights a potential clinical application of the presented polymeric platform.

Bioorthogonal catalysis offers a unique strategy to modulate biological processes through the in situ generation of therapeutic agents. However, the direct application of bioorthogonal transition metal catalysts (TMCs) in complex media poses numerous challenges due to issues of limited biocompatibility, poor water solubility, and catalyst deactivation in biological environments. We report here the creation of catalytic "polyzymes", comprised of self-assembled polymer nanoparticles engineered to encapsulate lipophilic TMCs. The incorporation of catalysts into these nanoparticle scaffolds creates water-soluble constructs that provide a protective environment for the catalyst. The potential therapeutic utility of these nanozymes was demonstrated through antimicrobial studies in which a cationic nanozyme was able to penetrate into biofilms and eradicate embedded bacteria through the bioorthogonal activation of a pro-antibiotic.

Infections caused by bacterial biofilms are challenging to diagnose because of the complexity of both the bacteria and the heterogeneous biofilm matrix. We report here a robust polymer-based sensor array that uses selective interactions between polymer sensor elements and the biofilm matrix to identify bacteria species. In this array, an appropriate choice of fluorophore enabled excimer formation and interpolymer FRET, generating six output channels from three polymers. Selective multivalent interactions of these polymers with the biofilm matrices caused differential changes in fluorescent patterns, providing a species-based signature of the biofilm. The real-world potential of the platform was further validated through identification of mixed-species bacterial biofilms and discrimination of biofilms in a mammalian cell-biofilm co-culture wound model.

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.

A glycan-stimulated and poly(3,4-ethylene-dioxythiophene)s (PEDOT)-based nanomaterial platform is fabricated to purify circulating tumor cells (CTCs) from blood samples of prostate cancer (PCa) patients. This new platform, phenylboronic acid (PBA)-grafted PEDOT NanoVelcro, combines the 3D PEDOT nanosubstrate, which greatly enhances CTC capturing efficiency, with a poly(EDOT-PBA-co-EDOT-EG3) interfacial layer, which not only provides high specificity for CTC capture upon antibody conjugation but also enables competitive binding of sorbitol to gently release the captured cells. CTCs purified by this PEDOT NanoVelcro chip provide well-preserved RNA transcripts for the analysis of the expression level of several PCa-specific RNA biomarkers, which may provide clinical insights into the disease., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Integration of antimicrobial polymeric nanoparticles into hydrogel materials presents a promising strategy to address multidrug-resistant biofilm infections. Here we report an injectable hydrogel loaded with engineered cationic antimicrobial polymeric nanoparticles (PNPs) for the effective topical treatment of severe wound biofilm infections. The PNPs demonstrated biofilm penetration and disruption, resulting in the eradication of resistant and persister cells that reside within the biofilm. Significantly, PNPs did not elicit resistance development even after multiple exposures to sub-therapeutic doses. In vitro studies showed PNPs significantly reduced prolonged inflammation due to infection and promoted fibroblast migration. These PNPs were then incorporated into Poloxamer 407 (P407) hydrogels and utilized as an inert carrier for PNPs to provide a controlled and sustained topical release of the antimicrobial nanoparticles at the wound area. In vivo studies using a mature (4-day) wound biofilm infection in a murine model mimicking severe human wound infections demonstrated provided 99% bacterial biofilm clearance and significantly enhanced wound healing. Overall, this work demonstrated the efficacy and selectivity of the antimicrobial polymer-loaded hydrogel platform as a topical treatment for difficult-to-treat wound biofilm infections. [Display omitted] • Polymeric nanoparticles provide effective platforms to address antibiotic-resistant wound biofilm infections. • Antimicrobial polymeric nanoparticles efficiently penetrate and eradicate bacterial biofilms without resistance development. • Controlled release of antimicrobial polymers is achieved through encapsulation within injectable thermoresponsive hydrogels. • Antimicrobial injectable hydrogels clear 99% of bacterial load and significantly enhance wound healing in vivo. [ABSTRACT FROM AUTHOR]

Intracellular pathogenic bacteria use immune cells as hosts for bacterial replication and reinfection, leading to challenging systemic infections including peritonitis. The spread of multidrug-resistant (MDR) bacteria and the added barrier presented by host cell internalization limit the efficacy of standard antibiotic therapies for treating intracellular infections. We present a non-antibiotic strategy to treat intracellular infections. Antimicrobial phytochemicals were stabilized and delivered by polymer-stabilized biodegradable nanoemulsions (BNEs). BNEs were fabricated using different phytochemicals, with eugenol-loaded BNEs (E-BNEs) affording the best combination of antimicrobial efficacy, macrophage accumulation, and biocompatibility. The positively-charged polymer groups of the E-BNEs bind to the cell surface of macrophages, facilitating the entry of eugenol that then kills the intracellular bacteria without harming the host cells. Confocal imaging and flow cytometry confirmed that this entry occurred mainly via cholesterol-dependent membrane fusion. As eugenol co-localized and interacted with intracellular bacteria, antibacterial efficacy was maintained. E-BNEs reversed the immunosuppressive effects of MRSA on macrophages. Notably, E-BNEs did not elicit resistance selection after multiple exposures of MRSA to sub-therapeutic doses. The E-BNEs were highly effective against a murine model of MRSA-induced peritonitis with better bacterial clearance (99 % bacteria reduction) compared to clinically-employed treatment with vancomycin. Overall, these findings demonstrate the potential of E-BNEs in treating peritonitis and other refractory intracellular infections. [Display omitted] [ABSTRACT FROM AUTHOR]