Navigation Links
New way to make malaria medicine also first step in finding new antibiotics
Date:9/26/2008

University of Illinois microbiology professor William Metcalf and his collaborators have developed a way to mass-produce an antimalarial compound, potentially making the treatment of malaria less expensive.

Metcalf set out to understand how this compound, one of a group known as phosphonates, is made in nature by bacteria. He was interested in that process partly because some phosphonates have antibiotic properties. Recently, Metcalf and his lab successfully identified and sequenced the genes and identified the processes by which bacteria make this particular phosphonate compound (FR900098).

His results are reported in the August 25 issue of Chemistry & Biology.

Although the compound has already been chemically synthesized, that is a costly process. By knowing how this phosphonate is biosynthesized, it can now be inexpensively mass-produced by harnessing the cellular machinery of bacteria.

"Malaria is a problem in Third World countries that can least afford expensive medicines, and many antibiotics are expensive," Metcalf said.

Efforts are already underway by Metcalf's colleague, chemical engineering professor Huimin Zhao, to engineer E. coli strains to overproduce FR900098, which can then be harvested for medicine.

In addition, says Metcalf, knowing the genes and understanding the pathway that bacteria use to make this antimalarial means the genes can be manipulated to make the compound even more effective against the malaria parasite while remaining harmless to people.

This effort to help treat malaria is just one facet of a major undertaking to find new antibiotics. Last year Metcalf and his colleagues at the U. of I.'s Institute for Genomic Biology, chemistry professor Wilfred van der Donk, Zhao, chemistry professor Neil Kelleher, and biochemistry professor Satish Nair, received a $7.3 million grant from the National Institutes of Health to investigate just this. Jo Handelsman of the University of Wisconsin rounds out the research team.

The need for new antibiotics is at an all-time high because multi-drug resistant bacteria are appearing even outside hospital settings. Consequently, infections that used to be easily curable have become more difficult to treat. For example, tuberculosis has become so resistant to antibiotics that soon "they'll send you to Arizona to drier air, like they did before they had antibiotics," Metcalf said.

In the case of malaria, the World Health Organization's "World Malaria Report 2008" estimates that "half of the world's population is at risk of malaria, and an estimated 247 million cases led to nearly 881,000 deaths in 2006."

Resistance to classic drugs such as chloroquine and sulphadoxine-pyrimethamine is on the rise, and mosquitoes also are developing resistance to insecticides.

"In my opinion malaria is the biggest single infectious disease problem in the world," Metcalf said.

The World Health Organization now advocates treating malaria with multiple antibiotics simultaneously, to combat the parasites' ability to develop resistance.

"In an infection, the chances are high that one in 10 million parasites in the patient's body will become resistant to a given drug," Metcalf said. "Now, if a patient takes a second drug simultaneously, one in 10 million parasites also becomes resistant to that drug. However, the odds that the same parasite will develop a resistance to both drugs is one in 10 million times one in 10 million, or 10 to the 14th."

This combination therapy approach is how HIV-AIDS, tuberculosis and other diseases are now treated. In the case of malaria, combination therapy both cures the patient and prevents wider infection, since an uninfected mosquito can acquire (and spread) the parasite by biting an infected person. But in many places where malaria is endemic, this approach is not used, in part because of the cost of medicine.

By making medicines more affordable it increases the chances that they will be used in the most effective way possible, that is to say, in combination with one another.

Metcalf became interested in anti-malarial medicine because of his interest in phosphonates, molecules that contain direct chemical bonds between carbon and phosphorus atoms (as opposed to the carbon-to-oxygen-to-phosphorus bonds that are found in most biological molecules containing phosphorus). As a doctoral student he characterized how microbes metabolized phosphonic acid in glyphosate, known commercially as RoundUp. He began to wonder where this class of compounds comes from and how it is made in nature.

In addition to sequencing the genes that make FR900098, Metcalf and his colleagues are focused on determining just how many naturally occurring phosphonic acids, or phosphonates, there are that have useful antibiotic, antifungal or anti-cancer properties.

The scientific community has known since the 1970s that bacteria routinely produce these types of phosphonates, in a kind of natural biological warfare.

"If you are a bacterium and you can kill off your neighbors you're better off yourself. It's kill or be killed," Metcalf said.

However, until now no one has done a systematic search for phosphonates in nature. Phosphonates work by disrupting biological pathways that use phosphate esters and organic acids. Each phosphonate disrupts a particular pathway. For example, FR900098 inhibits the pathway that creates isoprenoids, building blocks for important cellular components. When the parasites that cause malaria were discovered by others to have a pathway that FR900098 could disrupt, researchers saw a way to put the compound to good use. That same biosynthetic pathway does not exist in animals, which have a different way of making isoprenoids.

Understanding these pathways "opens the door to finding other antibiotics in this class of compounds. The more we can understand about these pathways the better we can find unknown phosphonates with antibiotic properties," Metcalf said.

His lab has developed a directed strategy to clone and sequence the genes that are required for phosphonate synthesis in bacteria, making the search efficient and exhaustive. Metcalf is optimistic that he and others will be able to mine phosphonates for other antibiotics.

"We've grown up in the Golden Age of antibiotics," he said. "But now kids can come home with an infection in their arm that can't be treated. And what happens if you can't treat it? You may have to amputate the arm. This is no joke; we better find new treatments."


'/>"/>

Contact: Melissa Edwards
mme@illinois.edu
217-333-0873
University of Illinois at Urbana-Champaign
Source:Eurekalert  

Related biology news :

1. NTDs burden in Latin America and the Caribbean may exceed that of HIV/AIDS, TB and malaria
2. Best way to treat malaria: Avoid using same drug for everyone, scientists say
3. Johns Hopkins scientists discover what drives the development of a fatal form of malaria
4. Research exposes new target for malaria drugs
5. Scientists demonstrate feasibility of preventing malaria parasite from becoming sexually mature
6. Netting mosquitoes to prevent malaria
7. Monkey malaria widespread in humans and potentially fatal
8. CWRU School of Medicine has evidence vaccine against malaria will reduce disease
9. Study of malaria parasite in patient blood finds distinct physiological states
10. Bug-Zapper: A dose of radiation may help knock out malaria
11. MSU researcher helps develop computer game for Ugandan children recovering from cerebral malaria
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
New way to make malaria medicine also first step in finding new antibiotics
(Date:4/19/2016)... 2016 The new GEZE SecuLogic ... web-based "all-in-one" system solution for all door components. It ... the door interface with integration authorization management system, and ... The minimal dimensions of the access control and the ... installations offer considerable freedom of design with regard to ...
(Date:4/14/2016)... , April 14, 2016 ... Malware Detection, today announced the appointment of Eyal ... new role. Goldwerger,s leadership appointment comes at ... heels of the deployment of its platform at several ... biometric technology, which discerns unique cognitive and physiological factors, ...
(Date:3/31/2016)... R.I. , March 31, 2016  Genomics firm ... of founding CEO, Barrett Bready , M.D., who ... members of the original technical leadership team, including Chief ... President of Product Development, Steve Nurnberg and Vice President ... returned to the company. Dr. Bready served ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... ... June 27, 2016 , ... Cancer experts ... they believe could be a new and helpful biomarker for malignant pleural mesothelioma. ... here to read it now. , Biomarkers are components in the blood, ...
(Date:6/27/2016)... Ginkgo Bioworks , a leading organism design company ... as one of the World Economic Forum,s Technology ... companies. Ginkgo Bioworks is engineering biology to manufacture ... the nutrition, health and consumer goods sectors. The ... Fortune 500 companies to design microbes for their ...
(Date:6/23/2016)... ... June 23, 2016 , ... Mosio, a leader ... “Clinical Trials Patient Recruitment and Retention Tips.” Partnering with experienced clinical research professionals, ... providing practical tips, tools, and strategies for clinical researchers. , “The landscape of ...
(Date:6/23/2016)... -- Houston Methodist Willowbrook Hospital has signed a ... serve as their official health care provider. As ... provide sponsorship support, athletic training services, and most ... athletes and families. "We are excited ... to bring Houston Methodist quality services and programs ...
Breaking Biology Technology: