The enzyme, DHPS, normally combines the molecules DHPP and pABA during part of a biochemical pathway that produces folate, a nutrient these bacteria need to survive.
The three-dimensional molecular image of the enzyme complex could unveil areas of the molecule that could be targeted by blocking molecules, according to the researchers, led by Stephen White of the St. Jude Children's Research Hospital.
The finding could become the basis for a broad-spectrum antibiotic to treat other infections that are becoming resistant to current drugs.
Researchers could also use the discovery to design more effective antibiotics against the bacterium, Bacillus anthracis. Such information is especially valuable because the anthrax bacterium is widely regarded as a potential bioterrorism weapon.
The discovery is additionally important since the pharmaceutical industry have been reducing its investment in developing new antibiotics. Whether voluntarily or involuntarily, academic institutions have taken on the mantle in filling the research gap ensuring effective treatments can be developed for future infections and diseases.
Scientists at St. Jude Children's Research Hospital made these discoveries by creating images of the molecular structure of DHPS using X-ray crystallography. Crystals of the enzyme were bombarded with X-rays and the patterns formed by the diffraction of the beams off the crystals created computer-generated, three-dimensional images of the enzyme shape.
The image showed that while this slight change in the shape of a small part of the enzyme made DHPS resistant to sulfa drugs, it did not disrupt the enzyme's ability to combine DHPP and pABA.
Stephen White, chairman of the St. Jude structural biology department said: "This subtle change is just enough to let DHPS prevent the antibiotic from binding to it, but not enough to disrupt the enzyme's normal work."
"So the bacteria evade the antibiotic and continue to make folate and survive," he added
The team also made a new drug-like molecule that binds to a part of the enzyme not likely to mutate and make the bacteria resistant to antibiotic molecules designed to bind there. This molecule (5-nitro-6-methylamino-isocytosine) binds to a part of DHPS deeper within the loops and folds of the protein structure of the enzyme than the sulfa-drug binding site.
Until now, no one had produced images of sulfa drugs binding to DHPS, which has severely limited research in this research area. Without that kind of visual information it's impossible to understand how the enzyme works, how the sulfa drugs interfere with DHPS and what kind of changes in the structure of DHPS make this enzyme resistant to sulfa drugs.
"If the drug binds to this part of DHPS, the enzyme would lose the ability to bind to DHPP and help the cell make folate," White said.
"If the enzyme mutated enough to avoid the antibiotic, the change in shape of this critical part of DHPS would destroy its ability to bind DHPP anyway. Either way, our new molecule looks like it could be the basis of a very effective new antibiotic against anthrax bacteria."
In addition, because many other infectious bacteria use DHPS to make folate, the St. Jude study holds promise for solving the growing problem of antibiotic resistance among microorganisms causing tuberculosis, pneumonia and a variety of other diseases.
US biotechnology companies Human Genome Sciences and Elusys Therapeutics, have developed similar anti-anthrax drugs, Abtrax and ETI-204 respectively. The drugs are artificial antibodies, or proteins that mimic the natural proteins made by the body to fight off invading germs.
Anthrax antibodies, though potentially useful, share one of the main disadvantages of current treatment with antibiotics in that its effectiveness appears to drop off rapidly the later they are administered in the course of the disease.