Supercomputer Simulations Help Develop New Approach to Fight Antibiotic Resistance

A joint UT-Oak Ridge National Laboratory research involving supercomputer simulations has played a key role in discovering a new class of drug candidates that hold promise to combat antibiotic resistance.

The study is co-authored by Jeremy Smith, the UT Governor’s Chair for Molecular Biophysics based in the Department of Biochemistry and Cellular and Molecular Biology. He also is director of the UT-ORNL Center for Molecular Biophysics. The work was done in partnership with ORNL, the University of Oklahoma, and Saint Louis University. Other UT researchers involved in the research include Jerry Parks, Jerome Baudry, and Adam Green.

The research was published in ACS Infectious Diseases.

The researchers combined lab experiments with supercomputer modeling to identify molecules that boost antibiotics’ effect on disease-causing bacteria. They found four new chemicals that seek out and disrupt bacterial proteins called “efflux pumps,” known to be a major cause of antibiotic resistance. Although some antibiotics can permeate the protective barriers surrounding bacterial cells, many bacteria have evolved efflux pumps that expel antibiotics back out of the cell and render the medications ineffective.

The team focused on one efflux pump protein, known as AcrA, which connects two other proteins in a tunnel shape through the bacterial cell envelope. Disrupting this centrally positioned protein could “throw a wrench” into the middle of the efflux pump and mechanically break it, unlike drug design strategies that try to inhibit overall biochemical processes.

“As a first in this field, we proposed the approach of essentially ‘screwing up’ the efflux pump’s protein assembly, and this led to the discovery of molecules with a new type of antibacterial activity,” Smith said. “In contrast to previous approaches, our new mechanism uses mechanics to revive existing antibiotics’ ability to fight infection.”

Read the full story on the Oak Ridge National Laboratory website.

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