MAR 20, 2018 11:10 PM PDT

The 'Molecular Key' in Developing Tuberculosis Drugs

WRITTEN BY: Nouran Amin

Tuberculosis is an ancient disease, signs of it were examined in Egyptian mummies. It is caused by the bacterium and pathogen, Mycobacterium tuberculosis, which infects about one quarter of the world's population killing roughly two million individuals per a year. Despite how ancient the disease is, the pathogen that causes Tuberculosis.

Now, research performed by scientists at the University of Rockefeller which is directed by Seth Darst and Elizabeth Campbell, a researcher in the Darst's laboratory, may challenge the evolutionary traits of M. tuberculosis offering a strong and potent treatment against the disease. The particular research has focused on an antibiotic that eradicates M. tuberculosis in a laboratory environment which is not suitable for clinical use. The researcher's work has aimed to explain how this new treatment operates which can encourage other investigators to develop new antibiotics to effectively treat tuberculosis patients.

Image via University of Cambridge

The discovered drug treatment was an antibiotic known as fidazomicin, which successfully kills M. tuberculosis. However, for fidazomicin to be effective against the treatment of tuberculosis in a real-world setting, it must be absorbed by the gut, and to do that researchers must understand its molecular mechanism.

Fidaxomicin works to inhibit an enzyme called RNA polymerase (RNAP), which helps transcribe DNA into RNA, a fundamental process of life. The enzyme, RNA polymerase, was seen to include hinged pincer that works to close down for secure DNA transcription. Therefore, investigators believe that fidaxomicin can interfere with the hinged pincer of the RNA polymerase, they just not yet understand how the interference occurs and if fidaxomicin holds inhibiting properties such knowledge may pride more versions of fidaxomicin for maximum efficacy against tuberculosis.

Through the use of an imaging technique known as cryo-electron microscopy, investigators were able to figure out exactly how the antibiotic works against RNAP. In early studies, they found out that a version of RNAP found in M. tuberculosis works only when combined with a protein known as RbpA; a transcription factor present in few bacteria. The transcription factor, RbpA, forms itself into a small pocket located at the base of the RNAP hinged pincer, allowing full functionality. Using cryo-electron microscopy, Hande Boyaci (a post-doc) and James Chen (graduate student) were able to make it evident that fidaxomicin binds to RbpA and other parts of the RNAP deep inside that pocket. "It acts like a doorstop, and prevents the clamp from securing DNA for transcription," says Elizabeth Campbell.

Furthermore, the research team took it a step furthers to work with a non-pathogenic cousin of M. tuberculosis; which is M. smegmatis. In particular, they used a mutant form of the bacterium that have a portion of the RbpA that is necessary for interaction with fidaxomicin. If the normal Mycobacteria was exposed to fidaxomicin, then the bacterium will not grow. On the other hand, the mutant forms were successful in dividing and thriving despite the presence of an antibiotic. This concluded that RbpA is essential in part of the mechanism which allows these un-mutated forms of Mycobacteria to be vulnerable to fidaxomicin.

"Our hope is that drug companies will use these studies as a platform for modifying and designing antimicrobials," says Campbell. "They could use the structures we analyzed to design antibiotics that would only inhibit Mycobacteria, but they could probably also design broad-spectrum antibiotics that would kill a wide range of other bacteria."

Sources: eLife, Science Daily

About the Author
  • Nouran earned her BS and MS in Biology at IUPUI and currently shares her love of science by teaching. She enjoys writing on various topics as well including science & medicine, global health, and conservation biology. She hopes through her writing she can make science more engaging and communicable to the general public.
You May Also Like
APR 15, 2020
Chemistry & Physics
APR 15, 2020
Could this drug help people with SAD?
Have you ever been sad in the winter? If so, you’re not alone. Medaka fish feel it too. Seasonal affective disorde ...
APR 10, 2020
Drug Discovery & Development
APR 10, 2020
Cancer Therapy Drug Reverses Kidney Damage
According to a study published in the journal Science Translational Medicine, a therapeutic previously used for cancer t ...
APR 30, 2020
Drug Discovery & Development
APR 30, 2020
Researchers Use AI to Accelerate COVID-19 Drug Development
Researchers from the National University of Singapore (NUS) have developed an artificial intelligence platform to accele ...
MAY 07, 2020
Immunology
MAY 07, 2020
New COVID-19 Vaccine Defends Monkeys Against Infection
Researchers from Beijing-based Sinovac Biotech have reported preliminary results of a study into the development of a va ...
MAY 11, 2020
Cancer
MAY 11, 2020
Using Deep Learning to Diagnose Breast Cancer Sub-Types
Cancer and computer programming may not sound like two things that go together. However, advanced programming techniques ...
MAY 25, 2020
Drug Discovery & Development
MAY 25, 2020
Potential Targets for Alcohol Induced Liver Disease
Alcohol-related liver disease (ALD) is a fatal condition targeting more than 150 million people. Part of what makes it d ...
Loading Comments...