Treatment of Mycobacterium tuberculosis infections is difficult, especially with the emergence of strains that are drug-resistant. Researchers led by University of Oklahoma professor Helen Zgurskaya are now working to find new, more effective drugs for tuberculosis.
Mycobacterium tuberculosis is a pathogenic bacterium that is implicated in the incidence of tuberculosis. Experts say it is the number one cause of infectious disease globally. It affects billions of people worldwide – about 25 percent of the world’s population.
Treatment of patients with active symptoms typically involves the use of multiple antibiotics for months. But, as with an increasing number of other bacterial infections these days, this infectious disease is becoming more drug-resistant.
“Currently, the treatment requires a combination of antibiotics taken by patients for six months, but now imagine that the disease does not respond to the treatment,” stated Zgurskaya, who is the study’s corresponding author and a George Lynn Cross Research Professor in the Department of Chemistry and Biochemistry in the Dodge Family College of Arts and Sciences.
“We are out of therapeutic options for this infection, and we need new drugs. The paper we published is focused on understanding how recently discovered new inhibitors kill the pathogen,” she added.
The new paper appeared in Proceedings of the National Academy of Sciences. Aside from OU scientists, its authors included researchers from Colorado State University, Creighton University, and the Georgia Institute of Technology.
MmpL3 and drug discovery
In this study, researchers investigated the mycobacterial membrane protein Large 3 (MmpL3) transporter and its analogs. This inner membrane protein is very critical for coming up with new drugs for tuberculosis.
MmpL3 transporters are vital for shuttling materials that are needed to build the outer membrane of Mycobacterium tuberculosis. They are, thus, essential for bacteria growth and building antibiotic resistance.
Zgurskaya and her colleague isolated MmpL3 from bacterial cells and purified it. Next, they reconstituted this major target for anti-tuberculosis discovery and its analogs in artificial membranes.
The team went further to make a range of substrate mimics and transporter-specific inhibitors. It also examined the activities and properties of these molecules.
Findings showed that all reconstituted proteins aided proton transfer across membranes. However, striking differences were observed in the responses of MmpL3 analogs to pH and their interactions with substrate mimics and indole-2-carboxamide inhibitors.
This new paper suggests that certain inhibitors stop the transport activity of MmpL3, together with its analogs, by blocking proton translocation.
This study creates a potent method for characterizing and making new drugs for tuberculosis.
The research lays the groundwork for working out the mechanism of MmpL3 transporters. It also provides a biochemical basis for grasping the inhibition of these transporters by tiny molecule compounds. This will hopefully prove crucial for developing new effective antibiotics for tuberculosis treatment.
The expected next step following the publication of this paper would be to use the developed methods to study other inhibitors, said Zgurskaya. This will help to know which ones are most effective for possible evaluation in clinical trials.