Melbourne Dental School - Research Publications
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ItemMultifunctional Antimicrobial Polypeptide-Selenium Nanoparticles Combat Drug-Resistant Bacteria(AMER CHEMICAL SOC, 2020-12-16)Antibiotic-resistant bacteria are a severe threat to human health. The World Health Organization's Global Antimicrobial Surveillance System has revealed widespread occurrence of antibiotic resistance among half a million patients across 22 countries, with Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae being the most common resistant species. Antimicrobial nanoparticles are emerging as a promising alternative to antibiotics in the fight against antimicrobial resistance. In this work, selenium nanoparticles coated with the antimicrobial polypeptide, ε-poly-l-lysine, (Se NP-ε-PL) were synthesized and their antibacterial activity and cytotoxicity were investigated. Se NP-ε-PL exhibited significantly greater antibacterial activity against all eight bacterial species tested, including Gram-positive, Gram-negative, and drug-resistant strains, than their individual components, Se NP and ε-PL. The nanoparticles showed no toxicity toward human dermal fibroblasts at the minimum inhibitory concentrations, demonstrating a therapeutic window. Furthermore, unlike the conventional antibiotic kanamycin, Se NP-ε-PL did not readily induce resistance in E. coli or S. aureus. Specifically, S. aureus began to develop resistance to kanamycin from ∼44 generations, whereas it took ∼132 generations for resistance to develop to Se NP-ε-PL. Startlingly, E. coli was not able to develop resistance to the nanoparticles over ∼300 generations. These results indicate that the multifunctional approach of combining Se NP with ε-PL to form Se NP-ε-PL is a highly efficacious new strategy with wide-spectrum antibacterial activity, low cytotoxicity, and significant delays in development of resistance.
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ItemStar-Peptide Polymers are Multi-Drug-Resistant Gram-Positive Bacteria Killers(AMER CHEMICAL SOC, 2022-06-08)Antibiotic resistance in bacteria, especially Gram-positive bacteria like Staphylococcus aureus, is gaining considerable momentum worldwide and unless checked will pose a global health crisis. With few new antibiotics coming on the market, there is a need for novel antimicrobial materials that target and kill multi-drug-resistant (MDR) Gram-positive pathogens like methicillin-resistant Staphylococcus aureus (MRSA). In this study, using a novel mixed-bacteria antimicrobial assay, we show that the star-peptide polymers preferentially target and kill Gram-positive pathogens including MRSA. A major effect on the activity of the star-peptide polymer was structure, with an eight-armed structure inducing the greatest bactericidal activity. The different star-peptide polymer structures were found to induce different mechanisms of bacterial death both in vitro and in vivo. These results highlight the potential utility of peptide/polymers to fabricate materials for therapeutic development against MDR Gram-positive bacterial infections.
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ItemCelogentin mimetics as inhibitors of tubulin polymerization(WILEY, 2020-03)Bicyclic analogues of celogentin C have been synthesized in which the side chain-side chain cross-links are replaced by thioether bonds. Several of the simplified bicyclic peptides displayed potent inhibition of tubulin polymerization.
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ItemPeripheral memory T-cell profile is modified in patients undergoing periodontal management(WILEY, 2021-02)AIMS: T-cells are known to have a role in periodontitis, however, the effect of periodontal therapy on peripheral memory T-cells is unclear. This study evaluated variation in peripheral memory T-cells and red complex bacteria in sub-gingival plaque in patients undergoing periodontal management. METHODS: Peripheral blood mononuclear cells and sub-gingival plaque were collected from 54 periodontitis patients at baseline, 3-, 6- and 12-months post-therapy and 40 healthy controls. Periodontitis patients were divided into treatment outcome (TxO) groups based on prevalence of sites with probing depth ≥5 mm as good (<10% of sites), moderate (10-20%) or poor (>20%) at study conclusion. Naïve (TN -CCR7+ CD45RA+ ), central memory (TCM -CCR7+ CD45RA- ), effector memory (TEM -CCR7- CD45RA- ) and effector memory T-cells re-expressing CD45RA (TEMRA -CCR7- CD45RA+ ) were phenotyped using flow cytometry in CD4+ , CD8+ , CD4+ CD8+ and CD4- CD8- T-cells and red complex bacteria were quantified using qPCR. RESULTS: At baseline, periodontitis subjects had significantly greater mean probing depths and Porphyromonas gingivalis proportions, lower TN but higher CD4+ TCM , CD8+ TCM , CD4+ CD8+ TEM and CD4- CD8- TEM cell proportions compared to health. Periodontal therapy decreased mean probing depths, P. gingivalis proportions, TEM and CD4+ and CD8+ TCM cells, but increased TN and CD4+ and CD8+ TEMRA cells. The T-cell profile in the good TxO group showed therapy-related changes in CD4+ TEM , and CD8+ TN and TEM cells, whereas, no changes were observed in the poor TxO group. CONCLUSION: Management and the reduction in red complex bacteria were associated with changes in peripheral memory T-cells in periodontitis.
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ItemPeripheral T helper cell profiles during management of periodontitis(WILEY, 2021-01)AIM: Periodontitis has been associated with other systemic diseases with underlying inflammation responsible for the shared link. This study evaluated longitudinal variation in peripheral T helper cells in periodontitis patients undergoing management over 1 year. MATERIALS AND METHODS: Periodontal parameters and peripheral blood mononuclear cells (PBMCs) were collected from 54 periodontitis patients at baseline, and 3-, 6- and 12-months post-treatment and 40 healthy controls. IFN-γ+ , IL-4+ , IL-17+ and Foxp3+ and their double-positive expression were identified in CD4+ and TCRαβ+ cells using flow cytometry. PBMCs were incubated with P. gingivalis, and IFN-γ, IL-4, IL-17 and IL-10 in cell supernatant were measured by ELISA. Cells and cytokines were also assessed based on clinical response to treatment where good (<10% of sites), moderate (10-20%) and poor (>20%) treatment outcome (TxO) groups had probing depths of ≥5 mm at study conclusion. RESULTS: IFN-γ+ cells were lower at baseline, and 3- and 6-months compared to health, whereas Foxp3+ cells were increased at 12-months compared to all preceding timepoints and health. The good TxO group showed treatment-related variation in IFN-γ+ and Foxp3+ cells, whereas the poor TxO group did not. IFN-γ and IL-17 cytokine expression in cell supernatants was significantly lower at baseline compared to health, and IFN-γ and IL-10 showed treatment-related decrease. CONCLUSION: This study suggests that IFN-γ+ and Foxp3+ cells may have a role in the systemic compartment in periodontitis. Periodontal management has local and systemic effects, and thus, assessment and management of periodontitis should form an integral part of overall systemic health.
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ItemPeripheral neutrophil phenotypes during management of periodontitis(WILEY, 2021-01)BACKGROUND AND OBJECTIVES: Neutrophils are emerging as a key player in periodontal pathogenesis. The surface expression of cellular markers enables functional phenotyping of neutrophils which have distinct roles in disease states. This study aimed to evaluate the effect of periodontal management on neutrophil phenotypes in peripheral blood in periodontitis patients over one year. MATERIALS AND METHODS: Peripheral blood and the periodontal parameters, mean probing depth and percentage of sites with bleeding on probing (%BOP), were collected from 40 healthy controls and 54 periodontitis patients at baseline and 3-, 6- and 12- months post-treatment. Flow cytometry was used to identify CD11b+ , CD16b+ , CD62L- and CD66b+ expression on neutrophils, neutrophil maturation stages as promyelocytes (CD11b- CD16b- ), metamyelocytes (CD11b+ CD16b- ) and mature neutrophils (CD11b+ CD16b+ ), and suppressive neutrophil phenotype as bands (CD16dim CD62Lbright ), normal neutrophils (CD16bright CD62Lbright ) and suppressive neutrophils (CD16bright CD62Ldim ). RESULTS: CD62L- expression decreased with treatment. No differences were observed in neutrophil maturation stages in health or disease upon treatment. Suppressive and normal neutrophils showed a reciprocal relationship, where suppressive neutrophils decreased with treatment and normal neutrophils increased with treatment. In addition, %BOP was associated with suppressive neutrophils. CONCLUSION: This study demonstrates that management of periodontitis significantly modifies distinct neutrophil phenotypes in peripheral blood. Suppressive neutrophils may play a role in the pathogenesis of periodontitis. However, their exact role is unclear and requires further investigation.
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ItemIdentification of a periodontal pathogen and bihormonal cells in pancreatic islets of humans and a mouse model of periodontitis(NATURE RESEARCH, 2020-06-19)Results from epidemiological and prospective studies indicate a close association between periodontitis and diabetes. However the mechanisms by which periodontal pathogens influence the development of prediabetes/diabetes are not clear. We previously reported that oral administration of a periodontal pathogen, Porphyromonas gingivalis (Pg) to WT mice results in insulin resistance, hyperinsulinemia, and glucose intolerance and that Pg translocates to the pancreas. In the current study, we determined the specific localization of Pg in relation to mouse and human pancreatic α- and β-cells using 3-D confocal and immunofluorescence microscopy and orthogonal analyses. Pg/gingipain is intra- or peri-nuclearly localized primarily in β-cells in experimental mice and also in human post-mortem pancreatic samples. We also identified bihormonal cells in experimental mice as well as human pancreatic samples. A low percentage of bihormonal cells has intracellular Pg in both humans and experimental mice. Our data show that the number of Pg translocated to the pancreas correlates with the number of bihormonal cells in both mice and humans. Our findings suggest that Pg/gingipain translocates to pancreas, particularly β-cells in both humans and mice, and this is strongly associated with emergence of bihormonal cells.