Researchers are using a combination of supercomputers and lab experiments to identify new drugs to fight off drug resistant bacteria. (Credit: Shutterstock)
Researchers have enlisted the help of supercomputers in finding new drug candidates to help combat antibiotic resistant bacteria.
Led by the University of Oklahoma, with the Department of Energy’s Oak Ridge National Laboratory, the University of Tennessee and Saint Louis University, scientists used lab experiments combined with supercomputer modeling to identify molecules that boost antibiotics’ effect on drug-resistant bacteria.
In the study the researchers discovered four new chemicals that seek out and disrupt efflux pumps, which are bacterial proteins known to be a major cause of antibiotic resistance.
Jeremy Smith, who serves as a UT–ORNL Governor’s chair and director of the UT–ORNL Center for Molecular Biophysics, explained the approach of the study.
“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,” he said in a statement. “In contrast to previous approaches, our new mechanism uses mechanics to revive existing antibiotics’ ability to fight infection.”
While 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 main focus of the study was AcrA, an efflux pump protein that connects two other proteins in a tunnel shape through the bacterial cell envelope. Disrupting the centrally located protein mechanically breaks the efflux pump, unlike drug design strategies that try to inhabit overall biochemical processes.
The team was able to scan large numbers of chemicals to predict and select which would be the most effective in preventing AcrA proteins from assembling properly using both experiments and protein simulations run on ORNL’s Titan supercomputer.
“The supercomputing power of Titan allowed us to perform large-scale simulations of the drug targets and to screen many potential compounds quickly,” Helen Zgurskaya, head of OU’s Antibiotic Discovery and Resistance Group, who led the study, said in a statement. “The information we received was combined with our experiments to select molecules that were found to work well, and this should drastically reduce the time needed to move from the experimental phase to clinical trials.”
Researchers were forced to screen various combinations of molecules and proteins to determine which ones fit well together, a process complicated by the protein’s dynamic nature. Researchers were able to create a virtual representation of the proteins, generated a series of protein ‘snapshots’ in their various configurations and used Titan to dock thousands of molecules to each snapshot and estimated how strongly each would interact with the protein.
While the study focused on a prototypical type of efflux pump found in Escherichia coli bacteria, the researchers believe that the antibiotic-reviving approach will be applicable to many Gram-negative bacteria.
The study titled, “Reviving Antibiotics: Efflux Pump Inhibitors that Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump,” was led by Zgurskaya and co-authored by UT-ORNL’s Smith, Jerry Parks and Jerome Baudry; UT’s Adam Green; OU’s Narges Abdali, Julie Chaney, David Wolloscheck and Valentin Rybenkov; and SLU’s Keith Haynes and John Walker. The research was supported by a National Institutes of Health grant.
The study, which was published in ACS Infectious Diseases, can be viewed here.
Filed Under: Drug Discovery
