Novel Class of Drugs May Inhibit Antibiotic Resistance in Bacteria

The National Institutes of Health recently funded a study which has led to the discovery of a novel class of drugs that will aid in the fight against antibiotic resistance.

On their quest to put an end to a threat that may change modern medicine as we know it, the researchers discovered four chemicals that disrupt AcrA, an efflux pump protein, that contributes to antibiotic resistance in bacteria. In their study, published in the American Chemical Society’s Infectious Disease journal, the authors write, “Efflux pump inhibitors (EPIs) are emerging alternative therapeutics that have the potential to revive the activities of existing antibiotics and to control the spread of antibiotic resistance.” Instead of trying to hinder the bacterial biochemical process like other drugs, the team focused on breaking the efflux pump by disrupting the protein.

Helen Zgurskaya, PhD, chemistry professor at the Oklahoma University College of Arts and Sciences, stated that, using a Titan supercomputer from Oak Ridge National Laboratory (ORNL), the group of scientists were able to “perform large-scale simulations of the drug targets and to screen many potential compounds quickly.” The group then used those results in combination with their experiments to “select molecules that were found to work well… this should drastically reduce the time needed to move from the experimental phase to clinical trials,” noted Dr. Zgurskaya.

According to a press release, to identify the chemicals that would disrupt AcrA proteins, the researchers scanned a multitude of chemicals, and “screened various combinations of molecules and proteins to determine which ones were most disruptive to [the proteins’] formation.” Afterwards, the researchers ran experiments to verify the that the final molecules they selected did indeed disrupt the AcrA, and can, in fact, restore antibiotic ability to fight bacteria.

Jeremy C Smith, PhD, ORNL Governor’s Chair and director of the Center for Molecular Biophysics, stated “In contrast to previous approaches, our new mechanism uses mechanics to revive an existing antibiotic’s ability to fight infection.”

The authors write, “The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes, and potentiate the activities of antibiotics in Escherichia coli and other Gram-negative bacteria. Our findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.”