ORCID Profile
0000-0002-7341-8921
Current Organisations
The Geological Survey of Norway (NGU)
,
Centenary Institute
,
University of Sydney
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Publisher: American Geophysical Union (AGU)
Date: 03-07-2020
DOI: 10.1029/2019GL086611
Publisher: Springer Science and Business Media LLC
Date: 07-10-2019
DOI: 10.1038/S41598-019-50748-2
Abstract: Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield s les with exceptionally potent activity against M. tuberculosis . Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis . The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania -derived bengamide B was non-toxic against human cell lines, synergised with rif icin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis . Thus, bengamides isolated from Tedania sp . show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis .
Publisher: Public Library of Science (PLoS)
Date: 10-12-2014
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.IJID.2016.12.024
Abstract: Tuberculosis (TB) continues to be a significant cause of mortality and morbidity worldwide. An estimated 2 billion in iduals are infected with Mycobacterium tuberculosis and annually there are approximately 10 million new cases of clinical TB and 1.5 million deaths. Currently available drugs and vaccines have had no significant impact on TB control. In addition, the emergence of drug resistant TB is considered a public health crisis, with some strains now resistant to all available drugs. Unfortunately, the growing burden of antibiotic resistance is coupled with decreased effort in the development of new antibiotics. Natural sources are attractive starting points in the search for anti-tubercular drugs because they are extremely rich in chemical ersity and have privileged antimicrobial activity. This review will discuss recent advances in the development of TB drug leads from natural products, with a particular focus on anti-mycobacterial compounds in late-stage preclinical and clinical development.
Publisher: Frontiers Media SA
Date: 22-08-2019
Publisher: Geological Society of America
Date: 2007
DOI: 10.1130/G23613A.1
Publisher: Cold Spring Harbor Laboratory
Date: 10-2020
DOI: 10.1101/2020.10.01.323105
Abstract: The development of safe and effective adjuvants is a critical goal of vaccine development programs. In this report, we defined the immunostimulatory profile and protective effect against aerosol Mycobacterium tuberculosis infection of vaccine formulations incorporating the semi-crystalline adjuvant δ-inulin (Advax). Advax formulated with CpG oligonucleotide and the QS-21 saponin (Advax CpQS ) was the most effective combination, demonstrated by the capacity of CysVac2/Advax CpQS to significantly reduce the bacterial burden in the lungs of M. tuberculosis -infected mice. CysVac2/Advax CpQS protection was associated with rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the induction of antigen-specific IFN-γ + /IL-2 + /TNF + polyfunctional CD4 + T cells in the lung. When compared to the highly potent adjuvant combination of monophosphoryl lipid A and dimethyldioctadecylammonium bromide (MPL/DDA), Advax CpQS imparted a similar level of protective efficacy yet without the profound stimulation of inflammatory cytokines and vaccination site ulceration observed with MPL/DDA. Addition of DDA to CysVac2/ Advax CpQS further improved the protective effect of the vaccine, which correlated with increased polyfunctional CD4 + T cells in the lung but with no increase in vaccine reactogenicity. The data demonstrate that Advax formulations can decouple protective tuberculosis immunity from reactogenicity, making them ideal candidates for human application. Advax adjuvant formulations improve pulmonary protection against aerosol Mycobacterium tuberculosis infection Different combinations of adjuvant components markedly influence the level of protection observed Protection is associated with the rapid influx of myeloid cells to the site of vaccination and the induction of antigen-specific polyfunctional CD4 + T cells in the lung. Advax formulations abrogate vaccine-site ulceration and inflammatory cytokine production
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.EJPS.2016.03.024
Abstract: Inhaled delivery of drugs incorporated into poly (lactic-co-glycolic acid) (PLGA) microparticles allows a sustained lung concentration and encourages phagocytosis by alveolar macrophages that harboring Mycobacterium tuberculosis. However, limited data are available on the effects of physicochemical properties of PLGA, including the monomer ratio (lactide:glycide) and molecular weight (MW) on the aerosol performance, macrophage uptake, and toxicity profile. The present study aims to address this knowledge gap, using PLGAs with monomer ratios of 50:50, 75:25 and 85:15, MW ranged 24 - 240kDa and an anti-tuberculosis (TB) drug, rifapentine. The PLGA-rifapentine powders were produced through a solution spray drying technique. The particles were spherical with a smooth surface and a volume median diameter around 2μm (span ~2). When the powders were dispersed using an Osmohaler(®) at 100L/min for 2.4s, the fine particle fraction (FPFtotal, wt.% particles in aerosol <5μm relative to the total recovered drug mass) was ranged between 52 and 57%, with no significant difference between the formulations. This result suggests that the monomer ratio and MW are not crucial parameters for the aerosol performance of PLGA. The phagocytosis analysis was performed using Thp-1 monocyte-derived macrophages. The highest rate of uptake was observed in PLGA 85:15 followed by 75:25 and 50:50 with about 90%, 80% and 70%, respectively phagocytosis over 4h of exposure. Furthermore, the cytotoxicity analysis on Thp-1 and human lung adenocarcinoma epithelial cells demonstrated that PLGA concentration up to 1.5mg/mL, regardless of the monomer composition and MW, were non-toxic. In conclusion, the monomer ratio and MW are not crucial in determining the aerosol performance and cytotoxicity profile of PLGA however, the particles with high lactide composition have a superior tendency for macrophage uptake.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.EJPB.2016.07.014
Abstract: Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68-76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.
Publisher: Copernicus GmbH
Date: 19-04-2022
DOI: 10.5194/EGUSPHERE-2022-139
Abstract: Abstract. Continental rifts can form when and where continents are stretched. If the driving forces can overcome lithospheric strength, a rift valley forms. Rifts are characterised by faults, sedimentary basins, earthquakes and/or volcanism. With the right set of weakening feedbacks, a rift can evolve to break a continent into conjugate rifted margins such as those found along the Atlantic and Indian Oceans. When, however, strengthening processes overtake weakening, rifting can stall and leave a failed rift, such as the North Sea or the West African Rift. A clear definition of continental break-up is still lacking because the transition from continent to ocean can be complex, with tilted continental blocks and regions of exhumed lithospheric mantle. Rifts and rifted margins not only shape the face of our planet, they also have a clear societal impact, through hazards caused by earthquakes, volcanism, landslides and CO2 release, and through their resources, such as fertile land, hydrocarbons, minerals and geothermal potential. This societal relevance makes an understanding of the many unknown aspects of rift processes as critical as ever.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-01-2021
Abstract: Tuberculosis is the leading cause of death worldwide from a single infectious agent, but vaccines developed to date have limited efficacy and pose safety concerns. Protein-based vaccines are a safe option but usually require powerful adjuvants. We present ex les of fully synthetic, self-adjuvanted protein vaccine constructs. These vaccines comprise a low-dose immune-stimulating adjuvant, covalently fused to the ESAT6 protein from Mycobacterium tuberculosis , the causative agent of tuberculosis. When administered by inhalation, the vaccines generated powerful immune responses and significant protection from M. tuberculosis in the lungs of mice. The synthetic strategy we describe represents a method that could be used to rapidly generate vaccines for preclinical testing against many diseases, including novel pathogens such as SARS-CoV-2.
Publisher: Elsevier
Date: 2023
Publisher: American Chemical Society (ACS)
Date: 12-02-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.5B00833
Abstract: Recent studies have demonstrated that efflux pumps of Mycobacterium tuberculosis (M. tb) provide a crucial mechanism in the development of drug resistant to antimycobacterial drugs. Drugs that inhibit these efflux pumps, such as verapamil, have shown the potential in enhancing the treatment success. We therefore hypothesized that the combined inhaled administration of verapamil and a first-line rifamycin antibiotic will further improve the treatment efficacy. An inhalable dry powder consisting of amorphous verapamil and crystalline rifapentine with l-leucine as an excipient was produced by spray drying. The in vitro aerosol characteristic of the powder, its microbiological activity and stability were assessed. When the powder was dispersed by an Osmohaler, the total fine particle fraction (FPFtotal, wt % of particles in aerosol <5 μm) of verapamil and rifapentine was 77.4 ± 1.1% and 71.5 ± 2.0%, respectively. The combination drug formulation showed a minimum inhibitory concentration (MIC90) similar to that of rifapentine alone when tested against both M. tb H37Ra and M. tb H37Rv strains. Importantly, the combination resulted in increased killing of M. tb H37Ra within the infected macrophage cells compared to either verapamil or rifapentine alone. In assessing cellular toxicity, the combination exhibited an acceptable half maximal inhibitory concentration (IC50) values (62.5 μg/mL) on both human monocytic (THP-1) and lung alveolar basal epithelial (A549) cell lines. Finally, the powder was stable after 3 months storage in 0% relative humidity at 20 ± 3 °C.
Publisher: Frontiers Media SA
Date: 07-03-2019
No related grants have been discovered for Diana Quan.