UNIVERSITY PARK, Pa. — A compound found in African wormwood — a plant used medicinally for thousands of years to treat many types of illness — could be effective against tuberculosis, according to a new study that is available online and will be published in the October edition of the Journal of Ethnopharmacology.
The team, co-led by Penn State researchers, found that the chemical compound, an O-methylflavone, can kill the mycobacteria that causes tuberculosis in both its active state and its slower, hypoxic state, which the mycobacteria enters when it is stressed.
Bacteria in this state are much harder to destroy and make infections more difficult to clear, according to co-corresponding author Joshua Kellogg, assistant professor of veterinary and biomedical sciences in the College of Agricultural Sciences.
While the findings are preliminary, Kellogg said the work is a promising first step in finding new therapies against tuberculosis.
"Now that we've isolated this compound, we can move forward with examining and experimenting with its structure to see if we can improve its activity and make it even more effective against tuberculosis," he said. "We're also still studying the plant itself to see if we can identify additional molecules that might be able to kill this mycobacterium."
Tuberculosis — caused by the bacteria Mycobacterium tuberculosis, or Mtb — is one of the world's leading killers among infectious diseases, according to the Centers for Disease Control and Prevention. There are about 10 million cases a year globally, with approximately 1.5 million of those being fatal.
While effective therapies exist for TB, the researchers said there are several factors that make the disease difficult to treat. A standard course of antibiotics lasts six months, and if a patient contracts a drug-resistant strain of the bacteria, it stretches to two years, making treatment costly and time consuming.
Additionally, the bacteria can take two forms in the body, including one that is significantly harder to kill.
"There's a 'normal' microbial bacterial form, in which it's replicating and growing, but when it gets stressed — when drugs or the immune system is attacking it — it goes into a pseudo-hibernation state, where it shuts down a lot of its cellular processes until it perceives that the threat has passed," Kellogg said. "This makes it really hard to kill those hibernating cells, so we were really keen to look at potential new chemicals or molecules that are capable of attacking this hibernation state."
Multiple species of the Artemisia plant have been used in traditional medicine for centuries, the researchers said, including African wormwood, which has been used to treat cough and fever. Recent studies in Africa have suggested that the plant also has clinical benefits in treating TB.
"When we look at the raw plant extract that has hundreds of molecules in it, it's pretty good at killing TB," Kellogg said. "Our question was: There seems to be something in the plant that's really effective — what is it?"
For their study, the researchers took raw extract of the African wormwood plant and separated it into "fractions" — versions of the extract that have been separated into simpler chemical profiles. They then tested each of the fractions against Mtb, noting whether they were effective or ineffective against the bacteria. At the same time, they created a chemical profile of all of the tested fractions.
"We also used machine learning to model how the changes in chemistry correlated with the changes in activity that we saw," Kellogg said. "This allowed us to narrow our focus to two fractions that were really active."
From these, the researchers identified and tested a compound that effectively killed the bacteria in the pathogen's active and inactive states, which the researchers said is significant and rare to see in TB treatments. Further testing in a human cell model showed that it had minimal toxicity.
Kellogg said the findings have the potential to open new avenues for developing new, improved therapeutics.
"While the potency of this compound is too low to use directly as an anti-Mtb treatment, it may still be able to serve as the foundation for designing more potent drugs," he said. "Furthermore, there appear to be other, similar chemicals in African wormwood that may also have the same type of properties."
The researchers said that in the future, more studies are needed to continue exploring the potential for using African wormwood for treating TB.
Co-authors from Penn State are R. Teal Jordan, research technologist and lab manager in veterinary and biomedical sciences, and Xiaoling Chen, graduate student in pathobiology. Also co-authors on the paper were Scarlet Shell, Maria Natalia Alonso, Junpei Xiao, Juan Hilario Cafiero, Trevor Bush, Melissa Towler and Pamela Weathers, all at Worcester Polytechnic Institute.
The National Institutes of Health's National Institute for Allergies and Infectious Disease and the U.S. Department of Agriculture's National Institute of Food and Agriculture helped support this work.
