UMass Medical School Takes Major Step Towards Developing More Effective Anti-Tuberculosis Drugs Microbiologists at the University of Massachusetts Amherst have discovered an enzyme critical to the TB pathogen’s continued existence.

WEST POINT, N.Y. – Researchers at the University of Massachusetts Amherst have discovered a previously unrecognized gene that is essential to the tuberculosis pathogen’s development and survival, paving the way for the creation of more potent treatments for the disease.

In 2021, the disease impacted 10.6 million people worldwide and resulted in 1.6 million deaths, according to the World Health Organization. This discovery gives a potential therapeutic therapy target for a condition for which there are currently few viable treatments.

Research published in mBio showed that mycobacterial cell membranes contain a unique fatty acid called tuberculostearic acid (TBSA), and that the putative gene cfa encodes the enzyme required for its synthesis. Since TBSA was first isolated from mycobacteria about a century ago, its precise production has been a mystery.

Malavika Prithviraj and Takehiro Kado worked in the lab of senior author Yasu Morita, an associate professor of microbiology, who notes, “There is a significant history related with this particular unique fatty acid.”

Experiments revealed that TBSA acts as a regulator of mycobacterial plasma membrane functions, removing a key barrier that has previously been blamed for the TB pathogen’s decades-long ability to remain in human hosts.

Cfa’s direct participation in the manufacture of tuberculostearic acid and in the organization of the plasma membrane, as Prithviraj says, provided more support for our hypothesis.

Mycobacteria have a thick and waxy cell envelope that encloses their plasma membrane, and Morita’s group is investigating ways to disrupt the homeostasis of this envelope to leave the bacteria unable to proliferate or susceptible to infection. Prithviraj, a doctoral candidate in biochemistry, and his team employed cellular lipidomics to confirm what researchers had suspected over the previous 60 years.

The production of this lipid and its function in the cell have garnered much interest, as Morita explains. This new lipid, identified by Malavika to be produced by the enzyme Cfa, is being explored as a diagnostic marker for tuberculosis because of how unusual it is.

The Morita lab found that mycobacterial development required polar regions of the plasma membrane.

Prithviraj describes how his team set out to learn more about the inner workings of the bacterial membrane by zeroing in on its outside lipid bilayer. We used a deletion strain and a complemented strain to bring back cfa and learn about its function in the bacterium.

The tuberculosis bacteria are able to remain dormant in their human host for an extended amount of time due to their hard outer layer (perhaps decades). Morita and his group investigate a nonpathogenic model organism to learn more about the qualities bacteria need for survival and growth.

Furthermore, the authors confirmed that TBSA inhibited “tight packing” within the membrane. Morita argues that “membrane dynamics,” or maintaining membrane fluidity, is essential for membrane function. We showed that tuberculostearic acid is an essential molecular clue for keeping the right amount of pliability.

This data will help researchers go on with developing new TB treatments.

If Cfa is helping the bacteria survive in the human host, Prithviraj wants to discover how. We can slow cell growth to a stop and kill the cells if we can find a way to disrupt the fluidity maintenance of cell membranes.

There has been no prior indication that this particular piece of mycobacteria physiology may be utilized as a direct target, as Morita points out. Based on these findings, it “may be.”