UAB Research Sheds New Light on Antibiotic Resistance

Researchers at UAB (University of Alabama at Birmingham) have discovered how rifamycins, a family of antibiotics commonly used in clinical treatment of tuberculosis, function to destroy bacteria. The findings, published in the current issue of Cell, may help combat antibiotic resistance by allowing drug manufacturers to make changes in the molecular structure of these antibiotics, making them more effective against drug-resistant bacteria.

Posted on August 18, 2005 at 12:00 p.m.

BIRMINGHAM, AL — Researchers at UAB (University of Alabama at Birmingham) have discovered how rifamycins, a family of antibiotics commonly used in clinical treatment of tuberculosis, function to destroy bacteria. The findings, published in the current issue of Cell, may help combat antibiotic resistance by allowing drug manufacturers to make changes in the molecular structure of these antibiotics, making them more effective against drug-resistant bacteria.

The research team, led by Dmitry Vassylyev, Ph.D., professor of biochemistry and molecular genetics at UAB, along with researchers at Ohio State University led by Irina Artsimovitch, Ph.D., studied two clinically important members of the rifamycin family, rifapentine and rifabutin.

Using powerful imaging technology called X-ray crystallography, Vassylyev’s team discovered how the antibiotics bound to and affected their target in bacteria, RNA polymerase, which is essential for bacteria to survive.

“There is an intricate network of interactions that govern how these drugs bind to their targets,” said Vassylyev. “This research gives us a better understanding of the nature of that binding and of how bacteria become drug resistant. In turn, this points the way to how we can modify rifamycins to overcome that resistance.”

In particular, Vassylyev says they discovered that rifapentine and rifabutin worked by facilitating release of a RNA polymerase-bound magnesium ion vital for activity. RNA polymerase is responsible for gene expression in a cell and without it bacteria will die. Vassylyev says the binding modes for each drug were different, yet both were effective in releasing the magnesium ion.

“This variation in how the drugs bound to RNA polymerase means that it may be possible to re-engineer rifamycins with small modifications so that the next generation of antibiotics will be more able to overcome drug-resistant bacteria,” Vassylyev said.

This research was supported by grants from the National Institutes of Health and from RIKEN Harima Institute in Japan. Vassylyev also collaborated with colleagues at the RIKEN Harima Institute and the Structural Biology Research Center of the High Energy Accelerator Research Organization in Ibaraki, Japan.