Systems Approach Used to Determine How TB Pathogen Circumvents Treatment

The success of Mycobacterium tuberculosis (Mtb) is attributed to its ability to adapt and withstand diverse stresses within host microenvironments. In an effort to better understand these adaptations, researchers at Institute for Systems Biology (ISB) used a data-driven model (EGRIN 2.0), which helped them identify a network within Mtb that allows it to tolerate and resist drug therapies. When the network is disrupted, researchers found that Mtb’s cells are unable to properly divide, compromising their cell wall—a key defense mechanism. 

“We have quite literally found a chink in Mtb’s armor,” said Nitin Baliga, corresponding author of the paper published in Cell Reports. “We took a systems approach to figure out how this pathogen circumvents treatment, and we found a targetable mechanism that we know helps it deal with stressful conditions.”

EGRIN 2.0 helped the team see how Mtb’s genes work together and are affected by their environment. It also identified a signaling system called MtrA that helps the pathogen grow in response to signals from a host’s body. The team also found that MtrA decreases the effectiveness of antibiotics used to treat TB.

“We believe this clears the way for developing a drug to effectively target and inhibit the essential mechanism of the MtrA signaling system, thus preventing Mtb to resist and tolerate treatment,” said Eliza Peterson, lead author of the paper. “These insights can also help with finding other drugs and/or multi-drug regimens important for treating TB.”

“TB can hide itself, making it difficult to kill,” Baliga added. “This powerful technology helps us build models that show us when and how it is doing that, to find new targets, and to understand how drugs work.”