UF researchers find potential malaria treatment may extend to Legionnaires' disease, botulism

May 7, 2009

GAINESVILLE, Fla. — University of Florida researchers have found that a potential strategy for treating malaria also extends to the bacteria behind maladies such as Legionnaires’ disease, Weil’s syndrome and botulism.

The work, by researchers at UF’s Institute of Food and Agricultural Sciences, hinges on some organisms’ ability to produce folate despite lacking one of the essential enzymes typically used to produce the compound.

As they report in the online edition of the Journal of Bacteriology, microbiologist Valérie de Crécy-Lagard and biochemist Andrew Hanson discovered that many bacteria use the same substitute for the enzyme as the parasite that causes malaria.

Folate, a vitamin best known for its importance to healthy pregnancies, is also essential to fueling the cell division that enables bacteria to spread.

Humans don’t have the biological process that produces folate, so drugs that disrupt the process are ideal candidates for disease treatments. Two widely used antibiotics, trimethoprim and sulfamethoxazole, use this approach.

“It had been a big mystery ever since we started decoding bacterial genomes—what are we not seeing that allows certain bacteria to produce folate even though they are missing an essential step in the process?” Crécy-Lagard said. “The answer had already been found in the parasite that causes malaria.”
In 2008, a team led by John Hyde at the University of Manchester discovered that the malaria parasite may bypass the need for the folate enzyme FolB, instead using another enzyme, called PTPS.

As one of their first steps, the UF researchers verified that the malaria parasite’s enzyme substitution would work in bacteria by replacing the regular gene for FolB in E. coli (the lab mouse of the bacteriology world) with the PTPS gene from the malaria parasite.

This was the first time that this substitution had been shown to work in a living creature. The previous malaria parasite experiments had only offered biochemical, “test-tube” evidence.

As a side note, de Crécy-Lagard said the PTPS gene-bearing E. coli will make the gene easier to study for antimalarial drug development than such work would be in the malaria parasite. While single-celled, the parasite is significantly more complex and harder to handle than bacteria.

The researchers then went on to discover which bacteria this substitution may apply to by conducting a genomic and biochemical analysis of many types of bacteria known to lack FolB. The exact number of bacterial species that lack FolB is not known because of the sheer number of bacteria species that exist.

While this leaves more room for exploration, there is also work to be done to uncover how many more complex organisms also use the PTPS substitution.

Diatoms, single-celled organisms that are a vital part of ocean ecosystems, are likely candidates, Hanson said.

“Folate is an essential ingredient to virtually all life,” Hanson said. “And we have a long road to travel before we fully understand it.”