About My Health Careers Internship MedBlogs Contact us
Medindia LOGIN REGISTER
Advertisement

Potential Mechanism to Kill Mycobacterium Tuberculosis Identified

by Chrisy Ngilneii on March 21, 2018 at 1:12 PM
Font : A-A+

Potential Mechanism to Kill Mycobacterium Tuberculosis Identified

Fidaxomicin (Fdx) is an antibiotic that kills the bacteria that cause tuberculosis (M. tuberculosis) in the laboratory, but is not suitable for clinical use. However, based on the mechanism of how the drug operates, future research may design new antibiotics that could in fact be used to treat tuberculosis patients, and might even work on other bugs.

A flawed candidate
Campbell explains that the antibiotic in question, fidaxomicin, is uncommonly adept at killing M. tuberculosis cultivated in the lab. To be useful against tuberculosis in the real world, however, an antibiotic must be absorbed by the gut and eventually reach the lungs when taken orally, something that fidaxomicin cannot do.

Advertisement


Fidaxomicin targets an enzyme called RNA polymerase (RNAP), which transcribes DNA into RNA, a process fundamental to life. The enzyme possesses a hinged pincer, or clamp, that swings shut to secure DNA for transcription.

Scientists suspected that the drug works by somehow interfering with this clamp. But they didn't know precisely how the molecule went about its job, knowledge that would be essential to creating more useful versions of fidaxomicin.
Advertisement

By using a powerful imaging technique known as cryo-electron microscopy, however, Campbell and her colleagues were able to figure out exactly how the antibiotic throws a wrench into RNAP.

Open wide
Thanks to earlier research, the team already knew that the version of the enzyme found in M. tuberculosis only works properly when combined with a protein called RbpA, a transcription factor not found in all bacteria. RbpA winds itself into a narrow pocket located at the base of the RNAP clamp, making it fully functional. Using cryo-EM, post-doctoral fellow Hande Boyaci and graduate student James Chen were able to show for the first time that fidaxomicin binds to RbpA as well as other parts of the RNAP deep inside that pocket.

What's more, they were able to pinpoint what happens when the two molecules come together: fidaxomicin physically jams the enzyme's clamp open and won't allow it to close.

"It acts like a doorstop, and prevents the clamp from securing DNA for transcription," says Campbell.

Endless possibilities
Next, Campbell and her associates went a step further. Working with a non-pathogenic cousin of M. tuberculosis called M. smegmatis, the team used a mutant form of the bacteria that lacked the part of RbpA that interacts with fidaxomicin. When exposed to fidaxomicin, normal Mycobacteria could not grow. The mutants, however, were able to thrive despite the presence of the antibiotic and went about multiplying as usual, confirming what the researchers already suspected: that RbpA is an essential part of the mechanism that makes these microbes vulnerable to the drug.

Medicinal chemists might be able to use this insight into how fidaxomicin works to design versions of the antibiotic that are absorbed through the gut, or to identify other drugs that also bind in the RNAP pocket and interact with RpbA. Antibiotics that require RbpA to work would be very useful since they would kill only the select group of bacteria that contain RbpA. Antibiotics that kill indiscriminately can cause significant collateral damage, wiping out benevolent bacteria and breeding resistance among more dangerous ones.

At the same time, because all bacterial RNAP possesses the same pocket that fidaxomicin uses as its binding site, drug developers might also be able to use the team's structural data to develop antibiotics that kill bugs that do not rely upon RbpA at all.

"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."

Source: Eurekalert
Advertisement

Advertisement
News A-Z
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Advertisement
News Category
What's New on Medindia
Memory Loss - Can it be Recovered?
International Day of Persons with Disabilities 2021 - Fighting for Rights in the Post-COVID Era
Effect of Blood Group Type on COVID-19 Risk and Severity
View all

Medindia Newsletters Subscribe to our Free Newsletters!
Terms & Conditions and Privacy Policy.

More News on:
Tuberculosis Tracheostomy Pleural Effusion Silicosis Screening Tests for Tuberculosis Fever Cough Symptom Evaluation Diet in Tuberculosis Stomach Tuberculosis Extra Pulmonary Tuberculosis 

Recommended Reading
Tuberculosis
Tuberculosis, caused by Mycobacterium tuberculosis, primarily affects the lung. It may spread to ......
Extra Pulmonary Tuberculosis
Extra pulmonary tuberculosis is infection of tissues and organs other than the lungs by ......
Renal Tuberculosis
Renal tuberculosis or tuberculosis of the kidney is a type of genitourinary tuberculosis that can .....
Diet in Tuberculosis
Patients with tuberculosis should eat a healthy diet so that they build up their immunity to fight ....
Cough Symptom Evaluation
Cough is a symptom of a condition usually affecting the respiratory tract. It may be acute or chroni...
Fever
Fever or Pyrexia is an elevation in normal body temperature. Causes of fever include infections, inj...
Pleural Effusion
Pleural effusion is the accumulation of fluid in the space between the two coverings (pleura) of the...
Screening Tests for Tuberculosis
Tuberculin skin test and Interferon – Release Assays are tests used to screen for tuberculosis....
Silicosis
Silicosis is a lung disease caused by inhalation of crystalline free silica dust. It is characterise...
Stomach Tuberculosis
Abdominal tuberculosis, which is a form of extrapulmonary tuberculosis, affects the gastrointestinal...

Disclaimer - All information and content on this site are for information and educational purposes only. The information should not be used for either diagnosis or treatment or both for any health related problem or disease. Always seek the advice of a qualified physician for medical diagnosis and treatment. Full Disclaimer

© All Rights Reserved 1997 - 2021

This site uses cookies to deliver our services. By using our site, you acknowledge that you have read and understand our Cookie Policy, Privacy Policy, and our Terms of Use