Melbourne Dental School - Research Publications
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ItemUsing inorganic nanoparticles to fight fungal infections in the antimicrobial resistant era(ELSEVIER SCI LTD, 2023-03-01)Fungal infections pose a serious threat to human health and livelihoods. The number and variety of clinically approved antifungal drugs is very limited, and the emergence and rapid spread of resistance to these drugs means the impact of fungal infections will increase in the future unless alternatives are found. Despite the significance and major challenges associated with fungal infections, this topic receives significantly less attention than bacterial infections. A major challenge in the development of fungi-specific drugs is that both fungi and mammalian cells are eukaryotic and have significant overlap in their cellular machinery. This lack of fungi-specific drug targets makes human cells vulnerable to toxic side effects from many antifungal agents. Furthermore, antifungal drug resistance necessitates higher doses of the drugs, leading to significant human toxicity. There is an urgent need for new antifungal agents, specifically those that can limit the emergence of new resistant species. Non-drug nanomaterials have primarily been explored as antibacterial agents in recent years; however, they are also a promising source of new antifungal candidates. Thus, this article reviews current research on the use of inorganic nanoparticles as antifungal agents. We also highlight challenges facing antifungal nanoparticles and discuss possible future research opportunities in this field. STATEMENT OF SIGNIFICANCE: Fungal infections pose a growing threat to human health and livelihood. The rapid spread of resistance to current antifungal drugs has led to an urgent need to develop alternative antifungals. Nanoparticles have many properties that could make them useful antimycotic agents. To the authors' knowledge, there is no published review so far that has comprehensively summarized the current development status of antifungal inorganic nanomaterials, so we decided to fill this gap. In this review, we discussed the state-of-the-art research on antifungal inorganic nanoparticles including metal, metal oxide, transition-metal dichalcogenides, and inorganic non-metallic particle systems. Future directions for the design of inorganic nanoparticles with higher antifungal efficacy and lower toxicity are described as a guide for further development in this important area.
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ItemOne step antimicrobial coatings for medical device applications based on low fouling polymers containing selenium nanoparticles(Elsevier, 2023-07-01)All indwelling and implantable medical devices are associated with a risk of infection, and antimicrobial technologies that can provide effective protection against pathogen colonization and biofilm formation over the lifetime of these devices are urgently required. Here, strategies that combine multiple layers of defense have emerged as particularly promising. We have combined a copolymer coating based on 2-hydroxypropyl acrylamide and N-benzophenone acrylamide with novel, optimally sized antimicrobial selenium nanoparticles (Se NPs). The photoreactive polymer allowed the crosslinking and covalent anchoring of the coating in a single step, and the exceptionally low attachment of bacteria was demonstrated. Our results also demonstrated that the incorporation of the antimicrobial Se NPs provides the coating with an additional bactericidal functionality towards the Gram-positive bacteria S. aureus and E. faecalis, which are widely recognized as the most prevalent pathogens linked to medical device-associated infections and more broadly nosocomial infections. The multiple layers of defense provided effective inhibition of the growth of both bacteria strains in areas where the coating had been removed, as well as in the supernatant. Moreover, our results demonstrate the feasibility to modulate the release of Se NPs from the coating by tailoring coating parameters such as the nanoparticle to polymer ratio. Our cytotoxicity study further confirmed the superior biocompatibility of Se NPs compared to the well-established silver nanoparticles over a broad concentration range. Our multifunctional coating approach is expected to be translated into medical device applications due to its ease of manufacture and effective antimicrobial protection.
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ItemNo Preview AvailableDetection and identification of amino acids and proteins using their intrinsic fluorescence in the visible light spectrum(ELSEVIER, 2023-11-22)The detection and identification of biomolecules are essential in the modern era of medical diagnostics. Several approaches have been established, but they have significant limitations such as laborious and time-consuming sample preparation, analysis, and the need to use external probes which provide adequate but not desired levels of accuracy and sensitivity. Herein, we have explored successfully a non-invasive technique to detect and identifybiomolecules such as amino acids and proteins by utilizing their intrinsic fluorescence. The developed confocal microscopy method revealed high and photostable emission counts of these biomolecules including amino acids (tryptophan, phenylalanine, tyrosine, proline, histidine, cysteine, aspartic acid, asparagine, isoleucine, lysine, glutamic acid, arginine) and proteins (HSA, BSA) when they are excited with a green laser. The fluorescence lifetime of the samples enabled the identification and distinction of known and blind samples of biomolecules from each other. The developed optical technique is straightforward, non-destructive and does not require laborious labeling to identify specific proteins, and may serve as the basis for the development of a device that would quickly and accurately identify proteins at an amino acid level. Therefore, this approach would open an avenue for precise detection in imaging and at the same time increases our understanding of chemical dynamics at the molecular level.
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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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ItemSystematic comparison of activity and mechanism of antimicrobial peptides against nosocomial pathogens(ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2022-03-05)The World Health Organisation has deemed several multi-drug resistant (MDR) nosocomial bacterial pathogens to be of significant threat to human health. A stark increase in morbidity, mortality and the burden to healthcare systems around the world can be attributed to the development of resistance in these bacteria. Accordingly, alternative antimicrobial agents have been sought as an attractive means to combat MDR pathogens, with one such example being antimicrobial peptides (AMPs). Given the reported activity of AMPs, including Pardaxin, MSI-78, dermaseptin-PC (DMPC) and Cecropin B, it is important to understand their activities and modes of action against bacteria for further AMP design. In this study, we compared these AMPs against a panel of nosocomial bacterial pathogens, followed by detailed mechanistic studies. It was found that Pardaxin (1-22) and MSI-78 (4-20) displayed the most pronounced antimicrobial activity against the tested bacteria. The mechanistic studies by membrane permeability and molecular dynamics simulation further confirmed the strong membrane interaction and structure of Pardaxin (1-22) and MSI-78 (4-20), which contributed to their potent activity. This study demonstrated a structure and activity guidance for further design of Pardaxin (1-22) and MSI-78 (4-20) as therapeutics against MDR pathogens. The different effects of DMPC (1-19) and Cecropin B (1-21) on membrane integrity and phospholipid membrane interactions provided critical information for the rational design of next-generation analogues with specificity against either Gram-negative or Gram-positive bacteria.
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ItemNo Preview AvailableThe effect of tailing lipidation on the bioactivity of antimicrobial peptides and their aggregation tendency Special Issue: Emerging Investigators(WILEY, 2023-08)Abstract Antimicrobial peptides (AMPs) are potentially powerful alternatives to conventional antibiotics in combating multidrug resistance, given their broad spectrum of activity. They mainly interact with cell membranes through surface electrostatic potentials and the formation of secondary structures, resulting in permeability and destruction of target microorganism membranes. Our earlier work showed that two leading AMPs, MSI‐78 (4–20) and pardaxin (1–22), had potent antimicrobial activity against a range of bacteria. It is known that the attachment of moderate‐length lipid carbon chains to cationic peptides can further improve the functionality of these peptides through enhanced interactions with the membrane lipid bilayer, inducing membrane curvature, destabilization, and potential leakage. Thus, in this work, we aimed to investigate the antimicrobial activity, oligomerization propensity, and lipid‐membrane binding interactions of a range of N‐terminal lipidated analogs of MSI‐78 (4–20) and pardaxin (1–22). Molecular modeling results suggest that aggregation of the N‐lipidated AMPs may impart greater structural stability to the peptides in solution and a greater depth of lipid bilayer insertion for the N‐lipidated AMPs over the parental peptide. Our experimental and computational findings provide insights into how N‐terminal lipidation of AMPs may alter their conformations, with subsequent effects on their functional properties in regard to their self‐aggregation behavior, membrane interactions, and antimicrobial activity.
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ItemNo Preview AvailableThe overview of antimicrobial peptide-coated implants against oral bacterial infections Special Issue: Emerging Investigators(WILEY, 2023-06)Abstract Dental implants are the most common therapeutic approach for resolving tooth loss and damage. Despite technical advances in treatment, implant failure rates can be as high as 23% with the major cause of peri‐implantitis: a multi‐species bacterial infection. With an annual growth rate in implant placements of 8.78% per annum, implant failure caused by bacterial infection is a significant oral and general health issue. The rise in antibiotic resistance in oral bacteria further adds pressure to implant failure; thus, there is a need for adjunctive therapy to improve implant outcomes. Due to the broad spectrum of activity and a low risk of inducing bacterial resistance, peptide antibiotics are emerging as a promising implant coating material to reduce/prevent peri‐implantitis and improve dental implant success rates. In this review, we summarised the current strategies of coating antimicrobial peptides (AMPs) onto dental implant material surfaces with multi‐functional properties to enhance osteoblast growth and prevent bacterial infections. This review compared the recent reported literature on dental implant coating with AMPs, which will provide an overview of the current dental implant coating strategies using AMPs and insights for future clinical applications.
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ItemNo Preview AvailableLabel-free macrophage phenotype classification using machine learning methods(NATURE PORTFOLIO, 2023-03-30)Macrophages are heterogeneous innate immune cells that are functionally shaped by their surrounding microenvironment. Diverse macrophage populations have multifaceted differences related to their morphology, metabolism, expressed markers, and functions, where the identification of the different phenotypes is of an utmost importance in modelling immune response. While expressed markers are the most used signature to classify phenotypes, multiple reports indicate that macrophage morphology and autofluorescence are also valuable clues that can be used in the identification process. In this work, we investigated macrophage autofluorescence as a distinct feature for classifying six different macrophage phenotypes, namely: M0, M1, M2a, M2b, M2c, and M2d. The identification was based on extracted signals from multi-channel/multi-wavelength flow cytometer. To achieve the identification, we constructed a dataset containing 152,438 cell events each having a response vector of 45 optical signals fingerprint. Based on this dataset, we applied different supervised machine learning methods to detect phenotype specific fingerprint from the response vector, where the fully connected neural network architecture provided the highest classification accuracy of 75.8% for the six phenotypes compared simultaneously. Furthermore, by restricting the number of phenotypes in the experiment, the proposed framework produces higher classification accuracies, averaging 92.0%, 91.9%, 84.2%, and 80.4% for a pool of two, three, four, five phenotypes, respectively. These results indicate the potential of the intrinsic autofluorescence for classifying macrophage phenotypes, with the proposed method being quick, simple, and cost-effective way to accelerate the discovery of macrophage phenotypical diversity.
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ItemNo Preview AvailableDirected chemical dimerisation enhances the antibacterial activity of the antimicrobial peptide MSI-78(4–20)(CSIRO Publishing, 2023-05-31)Antimicrobial resistance (AMR) is on the rise, leading to 700 000 deaths worldwide in 2020. Antimicrobial peptides (AMPs) are antibiotic agents that are active against multi-drug resistant pathogens and also have a reduced risk of AMR development. Previous studies have shown that dimerisation of the proline-rich antibacterial peptide (PrAMP) Chex1–Arg20 can enhance its antimicrobial activity while also reducing its toxicity. To determine if dimerisation via a simple disulfide bond can similarly improve other classes of AMPs, the α-helical cationic peptide MSI 78(4–20) was used as a model. The monomer alone, an S-carboxamidomethyl-capped N-terminal Cys–MSI-78(4–20) analogue and the disulfide-linked dimer were successfully synthesised and their antimicrobial activity and toxicity were determined. It was shown that dimerisation enhanced antimicrobial activity against the Gram-positive opportunistic pathogen Staphylococcus aureus ATCC 29213, the Gram-negative bacteria Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 47615. The peptides showed no significant haemolytic activity with red blood cells and only induced 50% lactate dehydrogenase (LDH) release in mammalian cells at the highest tested concentration, 15 µM. The MSI-78(4–20) dimer was less cytotoxic than the monomer and S-alkyl monomer. Together, the data support the strategy of AMP chemically directed dimerisation as a means of producing potentially more therapeutically useful antimicrobial agents.
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ItemBacteroides fragilis outer membrane vesicles preferentially activate innate immune receptors compared to their parent bacteria(FRONTIERS MEDIA SA, 2022-09-20)The release of bacterial membrane vesicles (BMVs) has become recognized as a key mechanism used by both pathogenic and commensal bacteria to activate innate immune responses in the host and mediate immunity. Outer membrane vesicles (OMVs) produced by Gram-negative bacteria can harbor various immunogenic cargo that includes proteins, nucleic acids and peptidoglycan, and the composition of OMVs strongly influences their ability to activate host innate immune receptors. Although various Gram-negative pathogens can produce OMVs that are enriched in immunogenic cargo compared to their parent bacteria, the ability of OMVs produced by commensal organisms to be enriched with immunostimulatory contents is only recently becoming known. In this study, we investigated the cargo associated with OMVs produced by the intestinal commensal Bacteroides fragilis and determined their ability to activate host innate immune receptors. Analysis of B. fragilis OMVs revealed that they packaged various biological cargo including proteins, DNA, RNA, lipopolysaccharides (LPS) and peptidoglycan, and that this cargo could be enriched in OMVs compared to their parent bacteria. We visualized the entry of B. fragilis OMVs into intestinal epithelial cells, in addition to the ability of B. fragilis OMVs to transport bacterial RNA and peptidoglycan cargo into Caco-2 epithelial cells. Using HEK-Blue reporter cell lines, we identified that B. fragilis OMVs could activate host Toll-like receptors (TLR)-2, TLR4, TLR7 and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), whereas B. fragilis bacteria could only induce the activation of TLR2. Overall, our data demonstrates that B. fragilis OMVs activate a broader range of host innate immune receptors compared to their parent bacteria due to their enrichment of biological cargo and their ability to transport this cargo directly into host epithelial cells. These findings indicate that the secretion of OMVs by B. fragilis may facilitate immune crosstalk with host epithelial cells at the gastrointestinal surface and suggests that OMVs produced by commensal bacteria may preferentially activate host innate immune receptors at the mucosal gastrointestinal tract.