HIV/AIDS, Malaria and Tuberculosis
Global mHealth (WelTel):
Clinical research interests include using mobile information technology (cell phones) to improve patient support and health services in resource-limited settings. This initial work in Kenya was featured on CBC’s The National, highlighted by the World Health Organization Essential Medicines Monitor, and published in Nature. This work represents the first comparative outcomes research showing effectiveness of mHealth for HIV and health outcomes in a developing world setting (published in The Lancet online Nov. 9th, 2010). We are working to scale up the project and expanding to include health conditions other than HIV.
Prevention, Diagnosis, and Treatment of HIV and TB in the Workplace:
With funds from the Global Health Research Initiative’s Canadian HIV Vaccine Initiative program, we are developing, implementing, and evaluating a program to build capacity in South Africa to implement and evaluate programs for prevention, diagnosis, and treatment of HIV and TB in the workplace. This project uses our online learning modules, as well as problem-based learning, but especially community-based learning, as all participants have to implement and evaluate HIV and TB in their own workplaces as part of their training.
Eradicating Disease through Democratic Models of Public Engagement
In the case of dengue and malaria, we will be using basic social sciences tools to better understand key actors and networks in disease management and control, while mapping those networks. This allows us to define disease in line with the perspectives of affected communities and to therefore design socially inclusive and effective tools for prevention, management and eradication in Mexico and Central America.
Through a multidisciplinary approach, we engage different players and stakeholders in order to be able to develop more inclusive and effective health policies and programs that can be managed through low cost, devolution and participatory models. This is the backbone for the 3
projects described below.
- Plant Extracts as Malaria & Dengue Solutions: Working in a multidisciplinary team to develop natural extracts from indigenous plants to produce insect repellants and very low toxicity insecticides for developing communities.
- “Getting Rid of Disease” Board Game for kids in order to disease awareness and develop basic participatory strategies and tactics for disease
prevention and management in poor communities. The focus is malaria, dengue and HIV.
- Low Cost Cellular Phone Health Education models through a collaboration scheme with IT, design and visual arts students in Latin & North America, focusing on dengue, malaria, HIV.
Low-Cost Malaria Diagnostic:
Accurate, sensitive, and cost-effective diagnostic tests are central to the global campaign to control and eradicate malaria. Inaccurate diagnosis not only results in patient mortality and morbidity, but also leads to ineffective use of treatment resources and could potentially accelerate the emergence of drug-resistant strains.
Malaria is caused by a protozoan parasite that invades human red blood cells. Currently, the gold standard detection method is the microscopic examination of Giemsa-stained blood smears to determine the density of infected red blood cells. This detection technique is sensitive and quantitative, but requires expertise and equipment often not available in low-resource regions. Rapid diagnostic tests based on immune-capture of antigens specific to the malaria parasite are a promising low-cost alternative. However, these tests are not as sensitive as microscopy, they do not provide a quantitative measure of parasite density, and they can produce a positive result even when parasites are no longer viable. We are developing a low-cost and portable device for detection of malaria infection that can quantitatively determine parasite density and discriminate viable and non-viable parasites. Such a device could be used to direct treatment until the clearance of all viable parasites, as well as to evaluate the effectiveness of new drugs and vaccines in clinical trials.
Ferrocenyl-carbohydrate Conjugates in Malaria:
Ferrocene has several properties which have facilitated its investigation for potential biological applications. Typically, organometallic compounds are sensitive to moisture and air, but ferrocene belongs to a unique group thereof whose members are stable under both aqueous and aerobic conditions. The small size, relative lipophilicity, easy chemical modification, and accessible one electron oxidation potential of ferrocene make it an attractive reporter moiety and an intriguing pharmaceutical vector. Ferrocenoyl carbohydrate conjugates have potential as metalloantimalarials. Combining the ferrocene moiety with a glucose derivative is a novel approach for developing targeted therapy. The ferrocene moiety has proven to be a successful addition to known malaria therapeutics, increasing efficacy towards chloroquine resistant strains of the parasite. As well, glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle and glucose consumption has been a target in anti-malarial research.
The hypothesis of this work is that ferrocene-carbohydrate conjugates have the potential to retain activity in chloroquine resistant parasite strains, and to have increased efficacy by targeting infected cells. This work studies the cytotoxicity and anti-plasmodial activity of several ferrocene carbohydrate conjugates, and includes the synthesis and characterization of numerous new ferrocene carbohydrate conjugates. With Dr. M. J. Adam of TRIUMF, we have published some preliminary studies showing that errocenyl carbohydrate conjugates exhibit some selective anti-malarial activity – glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle. The main goal of the project is to synthesize new ferrocenyl-carbohydrate conjugates that are inexpensive to produce, have activity in chloroquine-resistant parasites strains and that will have increased efficacy by targeting infected cells.
Synthesis of Antimalarial Agents:
We are currently working to develop new sets of chemical entities to treat malaria that will have activity against strains resistant to current medicines. We propose to achieve this through chemical modification that simplifies the core structure of the naturally occurring compound simaomicin a, an extremely potent antimalarial agent (0.045 ng/mL and 0.0097 ng/mL against the K1 and FCR3 strains respectively of Plasmodium falciparum). Current projects involve the synthesis of simaomicin a itself, as well as the generation of simplified analog structures.
Reducing malaria related child mortality in Uganda:
Defining a sustainable community self-management program In Uganda, it is estimated that more than 39,000 children less than five years of age die annually from malaria. Evidence suggests that over 50% of households purchase their drugs from unregulated drug vendors, which are often of questionable quality and/or incorrect dose and quantity. In partnership with Ugandan researchers, a community-based self-management intervention is being proposed to improve the practice of unregulated drug vendors and increase health literacy among caregivers. By focusing on improved access and use of antimalarial, this project’s aims are well aligns with the current UBC Neglected Global Disease.
Vikramaditya G. Yadav
Compounds for modifying mosquito behaviour:
Mosquito behavior modifying compounds such as attractants or repellents offer the greatest protection against the threat of mosquito bites. Unfortunately, the discovery of these molecules is largely empirical, painstakingly slow and often error‐prone. To this end, we are improving the speed and accuracy of compound identification by parallelizing compound synthesis and screening through the application of synthetic biology and robotic screening. The engineered microorganisms that synthesize the compounds of interest are subsequently employed in precisely controlled bioprocesses for sustainable and continuous manufacturing of the behavior modifying compounds.
New Therapeutic Drug Combinations for Tuberculosis Treatment:
Tuberculosis (TB) kills nearly 2 million people annually and 1/3 of all humans are infected. Co-infection with HIV and the emergence of resistant strains (MDR-, XDR- TB) has reaffirmed TB as a global public health threat. There are hundreds of drugs on the market, yet few are effective against TB. TB therapy is unpleasant and long (6-9 months). Curing MDR-TB can take up to 2 years, and there are no effective options for treating XDR-TB patients. New therapies are needed now.
Conventional drug discovery programs have focused on finding new compounds with novel targets but this has not been productive in recent decades. It takes ca.14 years/$800 million to bring a drug into the market. Our innovative approach focuses on a faster, more economical solution: To identify new synergistic combinatorial TB therapies using clinically approved drugs. Because these drugs have known pharmacokinetic and safety profiles, any newly identified combination can be rapidly evaluated in clinical trials.
The Centre for Tuberculosis Research
The Centre for Tuberculosis Research (CTBR):
The CTBR at UBC is dedicated to the development of novel therapeutics to curb the effects of the most devastating infectious agent of mortality worldwide, Mycobacterium tuberculosis (Mtb).
The Centre brings together researchers from the Faculty of Medicine (in the departments of Medicine, Pathology and Laboratory Medicine, Biochemistry and Molecular Biology) with colleagues from the Faculty of Science (in the department of Microbiology and Immunology).
The creation of the Centre allows these researchers to collaborate with each other, build upon each other’s strengths, exchange ideas and data across disciplines and create a stimulating training environment for graduate students and postdocs. The development and optimization of novel anti-bacterials is facilitated through working with the Centre for Drug Research and Development (CDRD).
Vision: To promote cutting-edge collaborative opportunities in the disciplines of microbiology, biochemistry, immunology and chemistry to better understand biological systems that can be used as targets for new drugs for tuberculosis chemotherapy.
1. To understand the scientific basis of Mtb’s prevalence, including its inherent resistance to antibiotics and its unusual ability to persist in the host.
2. To develop and optimize novel anti-bacterials that target Mtb.
Selected current projects:
1. Identification of new potential drug combinations to overcome the intrinsic resistance of M. tuberculosis.
2. Identification of M. tuberculosis enzymes that degrade cholesterol – a major nutrient source during infection.
3. Characterization of M. tuberculosis signalling proteins that disrupt host function.