Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors

Tag: malaria

Dennis Kyle: Finding Solutions for Deadly Diseases

Dennis Kyle
Dennis Kyle leads the UGA Center for Tropical and Emerging Diseases, and his endowment enables him to run a 16-person lab of student researchers, postdocs, and research scientists fighting a host of parasitic diseases around the world. (Photo by Andrew Davis Tucker/UGA)

GRA Endowment helps researchers save lives through drug discovery

The Amoeba Summit in Orlando last year is where the importance of her work on drug discovery for deadly amoebae really hit home for Cassiopeia Russell.

It was there she learned the story of an 11-year-old boy who had gone on a family vacation to Costa Rica and was having a great time going down a waterslide at a hot spring there. Days later, he started complaining of a terrible headache. Then he started vomiting. Within a week, he was dead. The cause was a microscopic organism, Naegleria fowleri, living in the warm waters of the spring.

Cassiopeia Russell
Cassiopeia Russell is a doctoral student working in Dennis Kyle’s lab on treatments to combat Naegleria fowleri, a rare but deadly brain-eating microscopic organism that can be 99% fatal if contracted. “This parasite infects mainly young children,” she says. “Hundreds have died.”

Russell, a doctoral student, had been working in the lab of Dennis Kyle, director of the UGA Center for Tropical and Emerging Global Diseases, for about a year when she was able to attend the conference thanks to a Georgia Research Alliance (GRA) endowment and learn how the research she does in the lab is making a real impact on people’s lives. The GRA was founded with the goal of expanding Georgia universities’ ability to conduct high-level research with the potential of bringing new and innovative products to market. Kyle is the GRA Eminent Scholar in Antiparasitic Drug Discovery, and his endowment enables him to run a 16-person staff of student researchers, postdocs, and research scientists.

“I asked myself at the beginning if I really wanted to work on a parasite this rare,” Russell says. “But if you look at the statistics, this parasite infects mainly young children. Hundreds have died.” She thinks about that every day in the lab.

More commonly referred to as the brain-eating amoeba, Naegleria fowleri is a surprisingly common amoeba found in warm water lakes, ponds, and rivers. When water is forced up the nose—like when diving into a body of water or repeatedly riding a waterslide—the parasite travels to the brain, where it attacks the organ’s cells. Though infections are rare, the brain-eating amoeba kills almost everyone it infects.

One reason Naegleria fowleri is so deadly is because symptoms of the infection resemble those of viral meningitis, a much more common and more treatable disease. “That misdiagnosis and waiting to see if the patient gets better after beginning treatment is wasting valuable time,” says Russell. She’s committed to finding faster, more effective ways to diagnose the condition so patients can get the right medications in time to stop the disease’s progression.

The Georgia Research Alliance really helped me set up this whole operation when I got here. Without the GRA, there’s no way that I could have had this team going for three years.” — Dennis Kyle, GRA Eminent Scholar in Antiparasitic Drug Discovery

As a member of Kyle’s lab, Russell also tests drug compounds to see which ones can kill an amoeba without destroying the human cells it infects. Current drugs used to treat the infection aren’t very effective and are highly toxic.

Despite being almost 99% fatal, not many federal dollars go toward research on brain-eating and other kinds of amoebae. That’s where the Georgia Research Alliance comes in.

“The Georgia Research Alliance really helped me set up this whole operation when I got here,” says Kyle. “Without the GRA, there’s no way that I could have had this team going for three years. This is something that we have concerns about in Georgia. Every summer, we hear of Naegleria fowleri cases on the news. But we don’t have many people worldwide working on it and very few doing the drug discovery needed to come up with a new drug that could save lives. And that’s really our goal.”

The other main area of research in the Kyle lab is malaria and how the parasite becomes resistant to the drugs commonly used to treat it. Additionally, a less commonly studied strain of malaria can go dormant inside its host, effectively hiding in the liver until flaring up weeks, months, or even years later. Kyle and his team were able to develop a model that simulates that dormant phase to test a variety of drugs to find a way to kill the parasite.

But in order to use that model, researchers in the lab must collect parasites from the field. The endowment helped the lab send assistant research scientist Steven Maher to Asia 25 times over the past four years to work with partners in Cambodia and Thailand.

“International travel has definitely changed my life,” Maher says. “Right now, we’re supporting people in Asia and their families, and I think having that human connection is really important. I think all too often we do research and we forget about ‘how is what I’m doing helping real people?’ I think a lot of researchers would benefit from that type of experience.”

The Georgia Research Alliance, private donors, and the UGA Athletic Association are committed to providing researchers like Russell and Maher with opportunities to advance their work on deadly infectious diseases threatening nations around the world.

Steven Maher with Cambodian colleagues
Assistant research scientist Steven Maher (far right) with the team he works with in Cambodia. GRA funding has allowed him to travel to Asia 25 times over the past four years battling malaria.

 

This article was originally published at https://news.uga.edu/dennis-kyle-finding-solutions-for-deadly-diseases/

Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints

The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring. Unfortunately, all the B- and C-ring analogs explored lost in vitro antimalarial activity. The possible role of steric effects and conformational changes on target engagement are discussed.

Sha Ding, Maryam Ghavami, Joshua H.Butler, Emilio F. Merino, Carla Slebodnick, Maria B. Cassera, Paul R. Carlier. Bioorg Med Chem Lett. 2020 Sep 5;127520. doi: 10.1016/j.bmcl.2020.127520

Trainee Spotlight: Alona Botnar

Alona Botnar

T32 trainee Alona Botnar is entering her fifth year as a Ph.D. candidate in Dr. Dennis Kyle’s laboratory. She is from Doylestown, Pennsylvania and completed her B.S. in Chemistry with a minor in Biochemistry at the University of Georgia in 2015. During her undergraduate career, she also worked at Janssen, a pharmaceutical company of Johnson & Johnson as a Biologics R&D co-op.

As a graduate student, she was able to spend three semesters teaching Anatomy and Physiology labs here at UGA, and in 2019, she was awarded the Outstanding Teaching Assistant Award sponsored by the Office of the Vice President for Instruction. She also received a graduate school travel award to attend the 2018 annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans, Louisiana, and an Office for Vice President and Research travel award to attend the 2020 Molecular Approaches to Malaria meeting held in Lorne, Victoria, Australia.

Why did you choose UGA?

Having been at UGA for my undergraduate degree, I was already in love with UGA and Athens and all that they have to offer. I was attracted to the Integrated Life Sciences program because it gives incoming graduate students the freedom to explore a wide range of research topics among 14 different departments before choosing the lab they would ultimately like to join. Furthermore, I found the interdisciplinary approach of the program appealing. I love the Center for Tropical and Emerging Global Diseases because of all the resources available to us as scientists. Not only do we have state of the art microscopy and flow cytometry cores, but we also have very collaborative labs that are happy to share equipment, supplies, and expertise.

What is your research focus?

My research is focused on malaria and addressing significant problems at the stages of development at which the malaria parasite enters a drug-induced dormant period and evades the antimalarial. The mechanism by which the parasite enters drug-induced dormancy and later recrudesces to continue development is currently unknown.

Half the world’s population is at risk of malaria with about half a million people dying each year from it. A majority of these deaths are in children under the age of 5, located mainly in sub-Saharan Africa. While there are 5 species that can infect humans, Plasmodium falciparum is the most lethal and is responsible for a majority of the deaths. Our current arsenal of malaria drugs is failing at an alarming rate as drug-resistant strains of the parasite continue to emerge.

Thus I chose this research project because it is vital that we respond to the challenge of antimalarial drug resistance by not only developing novel drugs but also by understanding the mechanisms the parasite is using to evade the drugs.

What are your future career goals?

I plan on continuing my work in the field of infectious diseases. I am leaning towards industry research but I’m keeping an open mind. Lately, I have been interested in alternative careers available to life science Ph.D.’s such as consulting and being a medical science liaison.

What is your favorite thing about UGA?

UGA football. There’s nothing quite like a fall Saturday in Athens between the hedges. GO DAWGS!

Do you have any advice for a student interested in this field?

It’s never too early or too late to get into the field. Don’t be afraid to send those emails and get involved in research. And always ask questions.

 

Support trainees like Alona by giving today to the Center for Tropical & Emerging Global Diseases.

[button size=’large’ style=” text=’Give Now’ icon=” icon_color=’BA0C2F’ link=’https://ctegd.uga.edu/give/’ target=’_self’ color=” hover_color=” border_color=” hover_border_color=” background_color=” hover_background_color=” font_style=” font_weight=” text_align=’center’ margin=”]

 

Age influences thermal tolerance in Asian malaria mosquito

Environmental portrait of Courtney Murdock in her laboratory at UGA’s School of Veterinary Medicine (Dorothy Kozlowski)

Malaria disease transmission models are important tools for controlling and eliminating disease spread. However, a model is only as good as the assumptions about the various variables. Dr. Courtney Murdock, a member of the UGA’s Center for Tropical and Emerging Global Diseases and professor at Cornell University, has been studying how various biological and environmental factors influence mosquito survival. In a study recently published in the Proceedings of the Royal Society B led by graduate student Kerri Miazgowicz, Murdock and her colleagues examined several life traits, such as biting, feeding, and egg production, over the course of the life span of the mosquito Anopheles stephensi in hopes of providing better data for the models.

“Due to a lack of high-quality entomological data in general, researchers are often forced to input data from multiple disease systems to inform models in a given system or use approximations of key model components,” said Murdock.

An. stephensi is the primary mosquito species that transmits malaria in India. While most of the focus on malaria is most often associated with sub-Saharan Africa, it is widespread in the Indian subcontinent and throughout southeast Asia. Several Plasmodium species cause malaria, but P. falciparum is the deadliest of them. It has also shown drug resistance to current treatments. Control of the mosquito population is an important component in malaria control and elimination programs. Researchers need to be able to more accurately predict where mosquito populations will occur as climate changes and current territories become unsuitable living and breeding grounds. Program managers need to be prepared to incorporate more northern regions in their control efforts.

trainee field work
Kerri Miazgowicz, a graduate student in the Murdock Laboratory at the University of Georgia, led the study on the effects of age on thermal tolerances.

Current models rely on data that are only snapshots in time and often from multiple mosquito species, particularly the African mosquitoes, which are vectors for different malaria species. Miazgowicz, Murdock, and colleagues wanted to determine if the data from a single species of mosquito and parasite, over the course of its entire lifespan, significantly influenced current models in determining disease transmission in hopes of creating more accurate models.

The single most important factor driving current models is temperature. Mosquitoes are cold-blooded animals and therefore rely on their environment to regulate their body temperature. However, temperature is not the only factor influencing life traits. Currently, data are only available as snapshots in time. These incomplete data do not take into account for changes in mosquito behavior and life traits that occur over the course of the mosquito’s life. Murdock and her colleagues have recorded changes in biological function as the mosquito ages. Just as people slow down biologically as they age – metabolism slows, reproduction ability declines, etc. – the same is true for mosquitos. They also found that various traits peak at different times depending on temperature. Importantly they found that temperature and age significantly affected the number of females taking a blood meal (this is the means in which malaria parasites are transmitted to humans) on a given day, average daily egg production, and ultimately survival.

The findings in this study indicated that the addition of An. stephensi data yielded qualitatively different temperature-transmission suitability relationships compared to models that included multiple malaria vectors. With An. stephensi data, the model predicted a broader geographical range of temperature suitability.

“Accounting for these age and species effects in models of transmission potential alters how much of South Asia is predicted to be suitable for malaria relative to models that do not account for these factors,” said Murdock.

These findings can lead to improved malaria transmission models. However, more study outside the laboratory is needed to truly understand the impact mosquito age has on life traits and thermal tolerance.

“This study highlights a critical need for more research in natural settings characterizing the effects of age on mosquito biology to improve predictions of current and future risk,” concluded Murdock.

 

Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

The cis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Interestingly, co-occurrence of polyprenols and dolichols, i.e. detection of a dolichol along with significant levels of its precursor polyprenol, are unusual in eukaryotic cells. Our metabolomics studies revealed that cis-polyisoprenoids are more diverse in the malaria parasite Plasmodium falciparum than previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was observed suggesting that cis-polyisoprenoid biosynthesis changes throughout parasite’s development. Moreover, we confirmed the presence of an active cis-prenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite.

Flavia M Zimbres, Ana Lisa Valenciano, Emilio F Merino, Anat Florentin, Nicole R Holderman, Guijuan He, Katarzyna Gawarecka, Karolina Skorupinska-Tudek, Maria L Fernández-Murga, Ewa Swiezewska, Xiaofeng Wang, Vasant Muralidharan, Maria Belen Cassera. Sci Rep. 2020 Aug 6;10(1):13264. doi: 10.1038/s41598-020-70246-0.

Pre-Erythrocytic Vaccines against Malaria

Malaria, caused by the protozoan Plasmodium, is a devastating disease with over 200 million new cases reported globally every year. Although immunization is arguably the best strategy to eliminate malaria, despite decades of research in this area we do not have an effective, clinically approved antimalarial vaccine. The current impetus in the field is to develop vaccines directed at the pre-erythrocytic developmental stages of Plasmodium, utilizing novel vaccination platforms. We here review the most promising pre-erythrocytic stage antimalarial vaccine candidates.

Camila Marques-da-Silva, Kristen Peissig, and Samarchith P. Kurup. Pre-Erythrocytic Vaccines against Malaria. Vaccines 20208, 400. https://doi.org/10.3390/vaccines8030400

Flavanones From the Twigs and Barks of Artocarpus Lakoocha Having Antiplasmodial and Anti-TB Activities

Chromatographic separation of the acetone extracts from the twigs and barks of Artocarpus lakoocha led to the isolation of the one new flavanone, lakoochanone (1), together with eleven known compounds (2-12). Lakoochanone (1) and moracin C (4) exhibited weak antiplasmodial activity against Plasmodium falciparum Dd2 with IC50 values of 36.7 and 33.9 µM, respectively. Moreover, moracin C (4) and sanggenofuran B (5) showed cytotoxic activity against A2780 cell line with the respective IC50 values of 15.0 and 57.1 µM. In addition, cyclocommunin (7) displayed strong antimycobacterial activity against Mycobacterium tuberculosis H37Ra with the minimum inhibitory concentration (MIC) value of 12.3 µM.

Sirada Boonyaketgoson, Yongle Du, Ana L. Valenciano Murillo, Maria B. Cassera, David G. I. Kingston, Kongkiat Trisuwan. Chem Pharm Bull (Tokyo). 2020;68(7):671-674. doi: 10.1248/cpb.c20-00080.

Bioactivity of Spongian Diterpenoid Scaffolds From the Antarctic Sponge Dendrilla antarctica

The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovaniPlasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B-D (1012). Chemical modification of abundant natural products led to three semisynthetic derivatives (1315), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.

Alexandre Bory, Andrew J Shilling, Jessie Allen, Ala Azhari, Alison Roth, Lindsey N Shaw, Dennis E Kyle, John H Adams, Charles D Amsler, James B McClintock, Bill J Baker. Mar Drugs. 2020 Jun 23;18(6):E327. doi: 10.3390/md18060327.

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

Martin J. McPhillie, Ying Zhou, Mark R. Hickman, James A. Gordon, Christopher R. Weber, Qigui Li, Patty J. Lee, Kangsa Amporndanai, Rachel M. Johnson, Heather Darby, Stuart Woods, Zhu-hong Li, Richard S. Priestley, Kurt D. Ristroph, Scott B. Biering, Kamal El Bissati, Seungmin Hwang, Farida Esaa Hakim, Sarah M. Dovgin, Joseph D. Lykins, Lucy Roberts, Kerrie Hargrave, Hua Cong, Anthony P. Sinai, Stephen P. Muench, Jitender P. Dubey, Robert K. Prud’homme, Hernan A. Lorenzi, Giancarlo A. Biagini, Silvia N. Moreno, Craig W. Roberts, Svetlana V. Antonyuk, Colin W. G. Fishwick, and Rima McLeod. Front. Cell. Infect. Microbiol., 09 June 2020 | https://doi.org/10.3389/fcimb.2020.00203