Researchers have discovered a new class of drugs that boosts the effect of antibiotics on disease-causing bacteria and holds promise for combating resistance to antibiotics.
“In contrast to previous approaches, our new mechanism uses mechanics to revive an existing antibiotic’s ability to fight infection,” said one of the researchers Jeremy Smith from University of Tennessee-Oak Ridge National Laboratory Center for Molecular Biophysics in the US.
Combining laboratory experiments with supercomputing modeling, the researchers identified four new chemicals that seek out and disrupt bacterial proteins called “efflux pumps”, a major cause of antibiotic resistance in bacteria, according to the study published in the American Chemical Society’s Infectious Diseases journal.
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.
The laboratory experiments were done jointly with extensive protein simulations run on Oak Ridge National Laboratory’s Titan supercomputer.
“The supercomputing power of ORNL’s Titan supercomputer allowed us to perform large-scale simulations of the drug targets and to screen many potential compounds quickly,” said Helen Zgurskaya, Professor at University of Oklahoma.
Large numbers of chemicals were scanned to predict and select which would be the most effective in preventing AcrA proteins from assembling properly.
Using computational models produced by the Titan supercomputer, the researchers screened various combinations of molecules and proteins to determine which ones were most disruptive to their formation.
The 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 Saint Louis University School of Medicine research team then synthesised structural analogs of the discovered efflux pump inhibitors and identified properties essential for their activities.
