New Anti-Malarial Drug Target

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An international team of scientists have identified the first reported inhibitors of a key enzyme involved in survival of the parasite responsible for malaria. Their findings, which may provide the basis for anti-malarial drug development, are currently published in the online version of the Journal of Medicinal Chemistry.

Tropical malaria is responsible for more than 1.2 million deaths annually. Severe forms of the disease are mainly caused by the parasite Plasmodium falciparum, transmitted to humans by female Anopheles mosquitoes. Malaria eradication has not been possible due to the lack of vaccines and the parasite’s ability to develop resistance to most drugs.

Led by researchers from the Department of Pediatrics at the University of California, San Diego School of Medicine, the team conducted high-throughput screening of nearly 350,000 compounds in the National Institutes of Health’s Molecular Libraries Small Molecule Repository (MLSMR) to identify compounds that inhibit an enzyme which plays an important role in parasite development: Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD) is essential for proliferating and propagating P. falciparum.

“The enzyme G6PD catalyzes an initial step in a process that protects the malaria parasite from oxidative stress in red blood cells, creating an environment in which the parasite survives,” said senior author Lars Bode, PhD, assistant professor in the UCSD Department of Pediatrics, Division of Neonatology and the Division of Gastroenterology, Hepatology and Nutrition. People with a natural deficiency in this enzyme are protected from malaria and its deadly symptoms, an observation that triggered the reported research.

The parasitic form of the enzyme (PfG6PD) is what contributes the majority of G6PD activity in infected red blood cells. Because the parasite lives in the blood of a malaria-infected person, the scientists aimed at identifying compounds that inhibit the parasitic form but not the human form of the enzyme. “We didn’t want to interfere with the human form of the enzyme and risk potential side effects,” Bode explained.

Scientific testing had previously been limited by a lack of recombinant PfG6PD. Team members in the lab of Katja Becker, PhD, at the Interdisciplinary Research Center at Justus-Liebig-University in Giessen, Germany produced the first complete and functional recombinant PfG6PD, and researchers led by Anthony Pinkerton, PhD, at Sanford-Burnham Medical Research Institute used it to identify the lead compound resulting from their efforts, ML276.

ML276 represents the first reported selective PfG6PD inhibitor, which stops the growth of malaria parasites in cultured red blood cells – even those parasites that developed resistance to currently available drugs. “ML276 is a very promising basis for future drug design of new anti-malarial therapeutics,” said Bode.

Contributors to the study include Janina Preuss, UC San Diego, Justus-Liebig-University and Sanford-Burnham Medical Research Institute; Esther Jortzik, Stefan Rahlfs and Katja Becker, Justus-Liebig-University; Patrick Maloney, Satyamaheshwar Peddibhotla, Paul Hershberger, Eliot Sugarman, Becky Hood, Eigo Suyama, Kevin Nguyen, Stefan Vasile, Arianna Mangravita-Novo, Michael Vicchiarelli, Danielle McAnally, Layton H. Smith. Gregory P. Roth, Michael P. Hedrick, Palak Gosalia, Monika Milewski, Yujie Linda Li, Eduard Sergienko, Jena Diwan, Thomas D.Y. Chung, and Anthony B. Pinkerton, Sanford-Burnham.

The study was supported by the National Institutes of Health (1R21AI082434), the Deutsche Forschungsgemeinschaft, and an NIH Molecular Libraries grant (U54 HG005033) to the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Medical Research Institute, one of the comprehensive centers of the NIH Molecular Libraries Probe Production Centers Network (MLPCN).

Source: University of California, San Diego Health Sciences

Genetically Engineered Bacteria Prevent Mosquitoes From Transmitting Malaria

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Researchers at the Johns Hopkins Malaria Research Institute have genetically modified a bacterium commonly found in the mosquito’s midgut and found that the parasite that causes malaria in people does not survive in mosquitoes carrying the modified bacterium. The bacterium, Pantoea agglomerans, was modified to secrete proteins toxic to the malaria parasite, but the toxins do not harm the mosquito or humans. According to a study published by PNAS, the modified bacteria were 98 percent effective in reducing the malaria parasite burden in mosquitoes.

“In the past, we worked to genetically modify the mosquito to resist malaria, but genetic modification of bacteria is a simpler approach,” said Marcelo Jacobs-Lorena, PhD, senior author of the study and a professor with Johns Hopkins Bloomberg School of Public Health. “The ultimate goal is to completely prevent the mosquito from spreading the malaria parasite to people.”

With the study, Jacobs-Lorena and his colleagues found that the engineered P. agglomerans strains inhibited development of the deadliest human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98 percent within the mosquito. The proportion of mosquitoes carrying parasites (prevalence) decreased by up to 84 percent.

“We demonstrate the use of an engineered symbiotic bacterium to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria,” said Jacobs-Lorena.

Malaria kills more than 800,000 people worldwide each year. Many are children.

The authors of “Fighting malaria with engineered symbiotic bacteria from vector mosquitoes” are Sibao Wang, Anil K. Ghosh, Nicholas Bongio, Kevin A. Stebbings, David J. Lampe and Marcelo Jacobs-Lorena.

The research was supported by National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, the Johns Hopkins Malaria Research Institute and the Bloomberg Family Foundation.

Source: Johns Hopkins Bloomberg School of Public Health

New Drug Synriam Approved to Treat Malaria in India

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A new drug to treat malaria, Synriam, was launched in India by Ranbaxy Laboratories Limited. The drug will provide additional options for malaria treatment as  traditional drugs become increasingly ineffective against the deadly malarial parasite because of acquired resistance to available medications.

Taken as a tablet once a day for three days, Synriam may be more effective, cheaper, and have fewer side effects and does not have to be taken with food, according to the University of Nebraska Medical Center (UNMC). From 2000 to 2010, Jonathan Vennerstrom, Ph.D., a professor at the UNMC College of Pharmacy, led an international team that created the drug compound that led to the development of Synriam. Developed by Ranbaxy Pharmaceuticals Limited, the medication now is approved for treatment in adults in India. The company also is working to create a children’s formula and make the drug available in Africa, Asia and South America.

“With more than 200 million cases of malaria each year, the potential impact this drug could have on saving and improving lives worldwide is significant,” Dr. Vennerstrom said. “That’s been our goal and now we are at the finish line.

Tim Wells, MMV’s chief scientific officer, said the completion of a phase III study in Indian adults and the approval of the combination by the Indian regulators was a major milestone. “We look forward to more data from patients in Africa and from studies with children, since this is where the vast majority of the disease is,” he said.

Courtney Fletcher, Pharm.D., dean of the UNMC College of Pharmacy, said another benefit of arterolane, the key component in the new drug invented by Dr. Vennerstrom, is it’s a synthetic. “This is an importance advance in antimalaria drugs. Since it’s a synthetic drug, it doesn’t depend on the availability of a natural plant source like some other antimalarials, which also makes it less expensive.”

Dr. Vennerstrom and his team also have developed a second drug candidate that might be even more superior than the first. It currently is being tested in phase II clinical trials by MMV in Bangkok, Thailand.

“This drug candidate seems to stay in the body longer, and therefore it may be possible to use a single dose instead of three doses,” Dr. Vennerstrom said. “We all forget to take our medications from time to time, so compliance becomes much easier when you have a single-dose drug.”

As a child of missionary parents working in Ethiopia, Dr. Vennerstrom took medications to prevent malaria.

Dr. Vennerstrom and his team received more than $12 million in grants from Medicines for Malaria Venture (MMV), a non-profit organization in Geneva, Switzerland. He has been studying malaria for more than 25 years. The research team included scientists at the Swiss Tropical and Public Health Institute in Switzerland and Monash University in Australia. MMV receives about 60 percent of its funding from the Bill and Melinda Gates Foundation.

“We were very fortunate to receive the support for our project from MMV,” he said. “It is always unpredictable whether or not a drug candidate will be successful.”

Source: University of Nebraska Medical Center (UNMC)

Researchers Discover Proteins in Mosquitoes that Help Fight Malaria Infection

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Researchers have discovered the function of a series proteins within the mosquito that transduce a signal that enables the mosquito to fight off infection from the parasite that causes malaria in humans. Together, these proteins are known as immune deficiency (Imd) pathway signal transducing factors, are analogous to an electrical circuit. As each factor is switched on or off it triggers or inhibits the next, finally leading to the launch of an immune response against the malaria parasite.

The latest study, conducted at the Johns Hopkins Malaria Research Institute, builds upon earlier work of the research team, in which they found that silencing one gene of this circuit, Caspar, activated Rel2, an Imd pathway transcription factor of the Anopheles gambiae mosquito. The activation of Rel2 turns on the effectors TEP1, APL1 and FBN9 that kill malaria-causing parasites in the mosquito’s gut. More significantly, this study discovered the Imd pathway signal transducing factors and effectors that will mediate a successful reduction of parasite infection at their early ookinete stage, as well as in the later oocyst stage when the levels of infection were similar to those found in nature.

“Identifying and understanding how all of the players work is crucial for manipulating the Imd pathway as an invention to control malaria. We now know which genes can be manipulated through genetic engineering to create a malaria resistant mosquito” said George Dimopoulos PhD, professor in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health.

To conduct the study, Dimopoulos’s team used a RNA interference method to “knock down” the genes of the Imd pathway. As the components were inactivated, the researchers could observe how the mosquito’s resistance to parasite infection would change.

“Imagine a string of Christmas lights or other circuit that will not work when parts aren’t aligned in the right sequence. That is how we are working with the mosquito’s immune system,” explained Dimopolous. “We manipulate the molecular components of the mosquito’s immune system to identify the parts necessary to kill the malaria parasites.”

Malaria kills more than 800,000 people worldwide each year. Many are children.

The authors of “Anopheles Imd pathway factors and effectors in infection intensity-dependent anti-Plasmodium action” are Lindsey S. Garver, Ana C. Bahia, Suchismita Das, Jayme A. Souza-Neo, Jessica Shiao, Yuemei Dong and George Dimopoulos.

The research was funded by the Johns Hopkins Malaria Research Institute and was published June 7, 2012 in the journal PLoS Pathogens.

Source: Johns Hopkins Bloomberg School of Public Health

President’s Malaria Initiative 2012

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April 25, 2012, marks World Malaria Day, a day designated to call attention to malaria and to mobilize action to combat it. The U.S. Government, on behalf of the American people, has taken extraordinary steps to curb the spread of this preventable and curable disease.

Since PMI’s launch in 2005, PMI has worked with partners in 15 high-burden countries in Africa to scale up effective malaria prevention and treatment interventions. In 2011, PMI expanded to four additional countries in Africa and the Greater Mekong Subregion. Eleven of the countries where PMI has been working have reported significant reductions in deaths among children under the age of five – ranging from 16 to 50 percent. There is strong and growing evidence that malaria prevention and control is a major factor in these reductions.

More information: President’s Malaria Initiative 2012 Executive Summary (PDF)

Source: President’s Malaria Initiative

New Partners Join the Asia Pacific Malaria Elimination Network (APMEN)

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The Asia Pacific Malaria Elimination Network (APMEN) has announced two new Partner Institutions have joined the organization: The Mahidol Vivax Research Center and the Malaria Research Centre, Universiti Malaysia Sarawak.

The Mahidol Vivax Research Center (MVRC) established in March 2011 is dedicated to the study of Plasmodium vivax and non falciparum malaria. Its establishment at Mahidol University in Thailand is important to the region, as Mahidol has a long record in the field of tropical disease medicine and research. Mahidol Vivax Research Center was initiated by the Dean of the Faculty of Tropical Medicine, Mahidol University, Associate Professor Pratap Singhasivanon and is directed by Dr. Jetsumon Prachumsri, formerly the leader of malaria research at the Armed Forces Research Institutes of Medical Sciences (AFRIMS) and APMEN Partner Institution representative.

The Malaria Research Centre was established at the Universiti Malaysia Sarawak in 2006 in recognition of the major contribution to malaria research by Professor Balbir Singh, Professor Janet Cox-Singh, and co-researchers at the Malaria Research Laboratory in the Faculty of Medicine and Health Sciences. MRC-UNIMAS is known for its work on Plasmodium knowlesi that was recognised by the World Health Organization (WHO) in 2008 as the fifth species of Plasmodia parasite to infect humans in the wild.

MRC-UNIMAS found that many malaria infections in Sarawak, Malaysia, had been incorrectly diagnosed and a major cause of malaria was Plasmodium knowlesi that is transmitted via the bit of an Anopheline mosquito from long-tail and pig-tail macaques. P knowlesi has also been reported in other parts of Malaysia, Indonesia, and Philippines and may be endemic in more countries in Southeast Asia. The final elimination of malaria in the Asia Pacific region will depend on a greater understanding of P knowlesi and how we can target this zoonosis.

The Malaria Research Centre, Universiti Malaysia Sarawak and the Mahidol Vivax Research Center have already supported APMEN through their active participation at last year’s annual meeting in Kota Kinabalu, Malaysia.

The fourth annual APMEN Annual Meeting will be held in May 2012 in Seoul, Republic of Korea. This year’s meeting will focus on how to sustain the gains made in the elimination of malaria and the importance in the coming years of maintaining successful approaches and their support. The region has many challenges to face in malaria elimination, in particular P. vivax, a type of malaria that is more difficult to diagnose and treat than P falciparum, the type of malaria most often discussed at a global level. APMEN through its information exchange, capacity building, and evidence building and advocacy activities is committed to supporting and maintaining elimination efforts in the Asia Pacific Region.

About the Asia Pacific Malaria Elimination Network
The Asia Pacific Malaria Elimination Network (APMEN) was established in 2009 to bring attention and support to the under-appreciated and little-known work of malaria elimination in Asia Pacific, with a particular focus on Plasmodium vivax.

APMEN is composed of 12 Asia Pacific countries (Bhutan, Cambodia, China, Democratic People’s Republic of Korea, Indonesia, Malaysia, Philippines, Republic of Korea, the Solomon Islands, Sri Lanka, Thailand, and Vanuatu) that are pursuing malaria elimination, as well as leaders and experts from key multilateral and academic agencies. The mission of this diverse but cohesive Network is to collaboratively address the unique challenges of malaria elimination in the region through leadership, advocacy, capacity building, knowledge exchange, and building the evidence base.

Development of the Network took place in 2008 through the leadership of the UCSF Global Health Group (GHG) and the School of Population Health, University of Queensland (SPH/UQ). APMEN collaborates closely with the WHO and is supported by the Australian Government through its international aid agency AusAID with a commitment of nearly $7 million for ongoing support to the Network. This complements Australia’s overall support for malaria control and elimination in the Asia Pacific and globally.

Source: Asia Pacific Malaria Elimination Network (APMEN)

Naturally Drug-Resistant Cave Bacteria Possible Key to New Antibiotics

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New research findings suggest the key to finding a whole new variety of antibiotics to treat drug-resistant infections may lie with the resident bacteria in one of the most isolated caves in the world.

The U.S. scientists who conducted the study say bacteria collected from Lechuguilla Cave in the state of New Mexico appear to possess an innate resistance to antibiotics, despite never having been exposed to any human sources.

Some of the bacteria had a pre-existing defense against as many as 14 different antibiotics. In all, the scientists say the cave-dwelling organisms showed a naturally-developed resistance to virtually every antibiotic currently used to treat bacterial infections.

While this may sound like bad news, the researchers explain that finding isolated, drug-resistant bacteria actually is a good thing. They say it suggests there are many types of previously unknown, naturally-occurring antibiotics in the environment that can be developed for doctors to use against currently untreatable infections.

First discovered 70 years ago, antibiotics are only effective against disease caused by bacterial infection. However, decades of widespread overuse, especially in agriculture industries, and via over-prescription by doctors, has made increasing types of disease-causing bacteria – so-called superbugs – immune to antibiotics.

There is increasing concern among scientists and medical experts that current antibiotic treatments could become completely ineffective against bacterial infections, which would be catastrophic for millions of people around the world suffering from diseases such as malaria.

Meanwhile, the scientists who conducted the new research point out that none of the Lechuguilla Cave bacteria used in their work are capable of making people sick.

The study was led by researchers from McMaster University and the University of Akron, both in the state of Ohio. A report on their findings is published in the journal, PLoS One (Public Library of Science One).

Bacteria are highly-adaptable microscopic single-cell organisms. One of Earth’s earliest life forms, evidence in the fossil record indicates bacteria have existed for about 3.5 billion years.

In addition to malaria, examples of other serious illnesses caused by bacterial infection include bubonic plague, tuberculosis, salmonella, and certain types of pneumonia and meningitis.

However, not all bacteria are bad or cause disease. Most are harmless to humans. Naturally-occurring bacteria in the human body help digest food, provide vital nutrients, fight cancer cells, and destroy disease-causing microbes.

Lechuguilla Cave was discovered in 1986. Since then, the U.S. Park Service has tightly restricted access to only a few scientific researchers and cave experts per year. Surrounded by a thick layer of watertight rock, the cave also is geologically isolated. The scientists say it can take up to 10,000 years for water to reach the inner-recesses of the cave where they collected the bacteria samples for their study.

Source: VOA News

World Malaria Day 2012

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“Sustain Gains, Save Lives: Invest in Malaria.”

World Malaria Day was established in May 2007 by the 60th session of the World Health Assembly, the decision-making body of the World Health Organization (WHO). The day was established to provide education and understanding of malaria and disseminate information on  malaria-control strategies, including community-based activities for malaria prevention and treatment in endemic areas.

According to the World Health Organization, approximately half the world’s population is at risk from malaria. And while malaria  is a preventable and treatable disease, it still claims the life of a child every minute, with more than 90% of all malaria deaths occurring in Africa. [Read more…]

New Optical Technique for Rapid Malaria Diagnosis

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Secondary Speckle Sensing Microscopy (S3M)

Secondary Speckle Sensing Microscopy (S3M). The difference between an infected red blood cell (top) and a healthy cell (bottom) is revealed by S3M, in part, by considering the dynamics of the correlation value (CV). CV indicates the similarity between two patterns. 1,000 CVs are calculated from pairs of consecutive speckles acquired in 1 second. As shown in the chart at right, the CV oscillation range for the infected cell (top, 0.36) is almost three times larger than that of the healthy red blood cell (bottom, 0.13). In the top left image of the infected cell a parasitic life-cycle stage of malaria, called “trophozoite,” can be seen (arrow). Credit: Dan Cojoc, Materials Technology Institute, National Research Council, Italy.

Correctly and quickly diagnosing malaria is essential for effective and life-saving treatment. But rapid detection, particularly in remote areas, is not always possible because current methods are time-consuming and require precise instrumentation and highly skilled microscopic analysis.

Now, a promising new optical imaging system, described in a paper published today in the Optical Society’s (OSA) open-access journal Biomedical Optics Express, may make the diagnosis of this deadly disease much easier, faster, and more accurate. [Read more…]

Drug-Resistant Malaria Threatens Effort to Control Disease

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A team of researchers from the United States and Thailand says the growing number of cases of drug-resistant malaria being reported in Thailand and neighboring countries threatens the worldwide campaign to control and eliminate the mosquito-borne disease. The malaria parasite in the region is becoming resistant to the first-line malaria therapy – artemisinin combination treatment – and experts say there is a real danger of the resistant strain moving to Africa, where malaria is widespread.

“The biggest fear is the resistance will spread across Southeast Asia and then spill over into Africa, where the vast majority of the 700,000 deaths a year [from malaria] occur. Historically, we have seen that when resistance to chloroquine [another anti-malaria drug] spread, there was an increase in mortality due to malaria. This is a very, very urgent situation,” said Tim Anderson, of the Texas Biomedical Research Institute, who spoke to us via Skype.

Anderson was part of the team that found evidence of growing resistance to artemesinin therapy for malaria in the border regions of Thailand and Burma, which they fear can spread westward across south east Asia and into Africa. The researchers are calling for immediate steps to control the spread of the resistant malaria parasite.

The number of malaria deaths dropped in the last few years because of the artemisinin combination treatment, and Anderson predicts that mortality figures will rebound if the drug loses its efficacy.

“We are seeing that the drug kills the parasite 100-fold less well than it used to. That doesn’t mean that the parasites are not killed, so we can still cure patients. But the concern is that the number of patients who are NOT cured will rise. We currently estimate that about 30 percent of the patients are not cured with artemisinin,” said Anderson.

“I have to say that I am not actually all that surprised. Every time we have developed a new drug, the parasite has figured out a way to get around it,” said Dr. David Kaslow, the director of the PATH Malaria Vaccine Initiative – an international nonprofit organization committed to developing a malaria vaccine.

“The good news is that the first-ever malaria vaccine is on the horizon,” said Kaslow.

The malaria vaccine could be available by 2015, Kaslow said. But it will be just one more weapon against malaria, and the problem of resistance to artemisinin is real.

“It is a piece of a larger control and – hopefully, some day – elimination and eradication program. We have to use a variety of tools – [including] bed nets, indoor residual spraying, and preventive therapy,” said Kaslow.

Experts say drug-resistant strains of malaria likely will continue to emerge. The solution, they believe, is to support the development of new drugs and new therapies to fight the disease.

Source: VOA News