Asian Scientist Magazine (Dec. 8, 2022) — Researchers across the world are on a hunt to discover a new drug to combat tuberculosis (TB), especially with the rising multi drug resistant (MDR) TB cases. In MDR-TB, the bacteria causing the disease are able to sneak through first-line TB treatment, rendering the otherwise life-saving treatment ineffective. In 2021, World Health Organization recorded 450,000 incident cases of MDR-TB globally. Of them, 37% cases were from Asia.
A team of researchers from Northeastern University in the US have extracted a compound from bacteria living in nematodes that target Mycobacterium tuberculosis—bacteria that causes TB. The findings of their study were published in Nature Chemical Biology.
Lead author of the study, Yu Imai, embarked on his quest to find an antimicrobial that selectively targets M. tuberculosis when he was a post-doc at the Lewis laboratory at Northeastern University.
“Broad-spectrum antibiotics are not ideal because there are possibilities that these compounds disturb our microbiome and generate drug-resistant mutants from off-target pathogen,” Imai told Asian Scientist Magazine. Imai is now an assistant professor in the Department of Biomolecular Innovation at Shinshu University, Japan.
Most antibiotics available in the market have been isolated from actinomycetes bacteria or fungi. But it’s increasingly getting “difficult to isolate novel antibiotics from these microbes because they have been overmined,” said Imai. So, his team thought of exploring the bacteria that reside in nematodes. They did so for a couple of reasons including that these bacteria – Xenorhabdus and Photorhabdus – have many antibiotic gene clusters in their genome. The researchers also wondered that the antibiotics the bacteria produce may not be toxic because they are living in nematode gut.
To find selective antibiotics from the cluster, the team tested out extracts from Xenorhabdus and Photorhabdus through differential screening. “We checked the activity of culture extracts against different types of pathogens,” such as Gram-positive bacteria M. tuberculosis, and S. aureus, bacteria that causes staphylococcus infection, said Imai.
If culture extracts hindered the growth of both pathogens, that meant that the extract contained broad-spectrum antibiotics against Gram-positive bacteria. But if the extract only acted against M. tuberculosis, it signalled that the antibiotic selectively targeted M. tuberculosis.
During their experiments, the researchers found that the compound extracted from the bacteria living in the nematodes only worked against mycobacteria, and didn’t affect other bacteria. The researchers name the compound evybactin.
Evybactin binds to DNA gyrase – an enzyme responsible for the synthesis of DNA – inside M. tuberculosis. When DNA gyrase is inhibited, the bacteria are not able to replicate.
The discovery and elucidation of evybactin is only the beginning. The researchers still need to take many steps to push evybactin to the market. The next step, according to Imai, is to test the movement and performance of evybactin inside animal models infected with M. tuberculosis.
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Source: Shinshu University ; Images: Shutterstock
The paper can be found at: Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis
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