Mitra S. Ganewatta

Antimicrobial metallopolymers and their bioconjugates with conventional antibiotics against multidrug-resistant bacteria.

Bacteria are now becoming more resistant to most conventional antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrug-resistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community settings by deactivating conventional β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, through various mechanisms, resulting in increased mortality rates and hospitalization costs. Here we introduce a class of charged metallopolymers that exhibit synergistic effects against MRSA by efficiently inhibiting activity of β-lactamase and effectively lysing bacterial cells. Various conventional β-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin, and cefazolin, are protected from β-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic cobaltocenium moieties. These discoveries could provide a new pathway for designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug-resistant bacteria and superbugs.

Antibacterial and Biofilm-Disrupting Coatings from Resin Acid-Derived Materials.

We report antibacterial, antibiofilm, and biocompatible properties of surface-immobilized, quaternary ammonium-containing, resin acid-derived compounds and polycations that are known to be efficient antimicrobial agents with minimum toxicities to mammalian cells. Surface immobilization was carried out by the employment of two robust, efficient chemical methods: Copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition click reaction, and surface-initiated atom transfer radical polymerization. Antibacterial and antibiofilm activities against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli were strong. Hemolysis assays and the growth of human dermal fibroblasts on the modified surfaces evidenced their biocompatibility. We demonstrate that the grafting of quaternary ammonium-decorated abietic acid compounds and polymers from surfaces enables the incorporation of renewable biomass in an effective manner to combat bacteria and biofilm formation in biomedical applications.

Bio-inspired resin acid-derived materials as anti-bacterial resistance agents with unexpected activities

Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrug resistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community-settings, resulting in increased mortality rates and hospitalization costs. Emergence of resistance even to vancomycin, the standard reference for MRSA treatment, builds up pressure for the search of novel alternatives. We report potent natural resin acid-based cationic antimicrobial compounds and polymers that exhibit surprising antimicrobial activity against a range of MRSA strains, yet are largely non-toxic against mammalian cells. Molecular dynamics simulations and dye-leakage assays with anionic phospholipid membrane mimics of bacteria demonstrate a membrane-lysing effect induced by unique fused ring structures of resin acids that may constitute the principal mechanism of action for selective lysis of bacterial cells over mammalian cells. Our antimicrobial materials are derived from an unlikely yet abundant natural source, and offer a novel alternative to currently-used approaches.

Plant Oil-Derived Epoxy Polymers toward Sustainable Biobased Thermosets

Epoxy polymers (EPs) derived from soybean oil with varied chemical structures are synthesized. These polymers are then cured with anhydrides to yield soybean-oil-derived epoxy thermosets. The curing kinetic, thermal, and mechanical properties are well characterized. Due to the high epoxide functionality per epoxy polymer chain, these thermosets exhibit tensile strength over an order of magnitude higher than a control formulation with epoxidized soybean oil. More importantly, thermosetting materials ranging from soft elastomers to tough thermosets can be obtained simply by using different EPs and/or by controlling feed ratios of EPs to anhydrides.

Blockade of CB1 cannabinoid receptor alters gut microbiota and attenuates inflammation and diet-induced obesity

Obesity is characterized by chronic low-grade, systemic inflammation, altered gut microbiota, and gut barrier disruption. Additionally, obesity is associated with increased activity of endocannabinoid system (eCB). However, the clear connection between gut microbiota and the eCB system in the regulation of energy homeostasis and adipose tissue inflammation and metabolism, remains to be established. We investigated the effect of treatment of mice with a cannabinoid receptor 1 (CB1) antagonist on Diet-Induced Obesity (DIO), specifically whether such a treatment that blocks endocannabinoid activity can induce changes in gut microbiota and anti-inflammatory state in adipose tissue. Blockade of CB1 attenuated DIO, inflammatory cytokines and trafficking of M1 macrophages into adipose tissue. Decreased inflammatory tone was associated with a lower intestinal permeability and decreased metabolic endotoxemia as evidenced by reduced plasma LPS level, and improved hyperglycemia and insulin resistance. 16S rRNA metagenomics sequencing revealed that CB1 blockade dramatically increased relative abundance of Akkermansia muciniphila and decreased Lanchnospiraceae and Erysipelotrichaceae in the gut. Together, the current study suggests that blocking of CB1 ameliorates Diet-Induced Obesity and metabolic disorder by modulating macrophage inflammatory mediators, and that this effect is associated with alterations in gut microbiota and their metabolites.

CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice

Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short‐chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT) mice, into EAE‐induced CD44WT mice, led to significant amelioration of EAE. High‐throughput bacterial 16S rRNA gene sequencing, followed by clustering sequences into operational taxonomic units (OTUs) and biochemical analysis, revealed that EAE‐induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE‐induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). Further, data showed a significant change in the abundance of SCFAs, propionic acid, and i‐butyric acid in EAE‐CD44KO compared to EAE‐CD44WT mice. In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota and SCFAs. Furthermore, our studies also demonstrate that the phenotype of gene knock‐out animals may be shaped by gut microbiota.

Facially amphiphilic polyionene biocidal polymers derived from lithocholic acid

Bacterial infections have become a global issue that requires urgent attention, particularly regarding to emergence of multidrug resistant bacteria. We developed quaternary amine-containing antimicrobial poly(bile acid)s that contain a hydrophobic core of lithocholic acid in the main-chain. Interestingly, by choosing appropriate monomers, these cationic polymers can form core-shell micelles. These polymers exhibited biocidal activity against both Gram-positive and Gram-negative bacterial species. It is demonstrated that the micelles can deliver hydrophobic antibiotics that functionally have dual antimicrobial activities. Cytotoxicity assays against HeLa cells showed dosage-dependent toxicity for polymers with longer linkers.