New class of drugs holds promise for combating antibiotic resistance


       A new class of drugs that combat antibiotic resistance has been discovered by a University of Oklahoma researcher and his team. In the study supported by the National Institutes of Health, laboratory experiments were combined with supercomputing modeling to identify molecules that boost the effect of antibiotics on disease-causing bacteria.

       Helen Zgurskaya, professor of chemistry and biochemistry in the OU College of Arts and Sciences, and OU team members Narges Abdali, Julie Chaney, David Wolloscheck and Valentin Rybenkov, collaborated with Jeremy Smith, Jerry Parks and Jerome Baudry, the University of Tennessee-Oak Ridge National Laboratory Center for Molecular Biophysics; Adam Green, UT; and Keith Haynes and John Walker, Saint Louis University School of Medicine. They collectively identified four new chemicals that seek out and disrupt bacterial proteins called "efflux pumps," a major cause of antibiotic resistance in bacteria.

       The supercomputing power of ORNL's Titan supercomputer had allowed them to perform large-scale simulations of the drug targets and to screen many potential compounds quickly said Zgurskaya, head of the OU Antibiotic Discovery and Resistance Group at the Stephenson Life Sciences Research Center. She added that the information received by stimulations was combined with their experiments to select molecules that were found to work well and that drastically reduced the time needed to move from the experimental phase to clinical trials.


       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 protein could essentially break the efflux pump, an approach unlike other drug design strategies that try to inhibit the biochemical processes.


       "In contrast to previous approaches, our new mechanism uses mechanics to revive an existing antibiotic's ability to fight infection," said Smith, UT-ORNL Governor's Chair and director of the UT-ORNL Center for Molecular Biophysics.


      Using computational models produced by the Titan supercomputer, researchers screened various combinations of molecules and proteins to determine which would be the most effective in preventing AcrA proteins from assembling properly.  


      "The first screening took only 20 minutes using 42,000 processors and yielded several promising results," said Parks, ORNL. "After more extensive analysis, we narrowed down our list to predict which molecules were most likely to disrupt the function of the efflux pump." he added.  


      OU researchers then conducted laboratory experiments to confirm the disruption of the efflux pump and the antibiotic-reviving capability of four of the molecules selected. The SLU School of Medicine research team synthesized structural analogs of the discovered efflux pump inhibitors and identified properties essential for their activities.  



(Image Credit: Oak Ridge National Laboratory)


      Once antibiotics have entered the cell by crossing the outer membrane (inset, top), they enter the efflux pump protein shown in yellow near the inner membrane (bottom) only to be pumped back out of the cell (upward). The Titan supercomputer identifies molecules that target the "red" proteins and potentially disable the efflux pump by preventing it from assembling properly.  


ENVIS CENTRE Newsletter Vol.14, Issue 4, Oct - Dec, 2016
Copyright © 2005 ENVIS Centre ! All rights reserved This site is optimized for 1024 x 768 screen resolution Query Form | Feedback | Privacy