Recent research by Erika A. Taylor, associate professor of chemistry, suggests that the way scientists have long believed some antibiotics used to treat bacterial infections work could be incorrect.
Aminoglycoside antibiotics have broad-spectrum, bacterial killing abilities and are often prescribed for childhood infections caused by Gram-negative bacterial pathogens, which can be found in E. coli, Salmonella, and V. cholera, amongst others.
The stakes of the research are real, Taylor explained. Improved antibiotics would prevent needless deaths from E. coli, Salmonella and other Gram-negative bacteria. Relatively simple treatments, such as those for urinary tract infections, would be more efficient, improving people’s quality of life.
“I am excited about the prospect of rewriting the story on how these antibiotics work, since new insights for the mechanism of action of these drugs could enable their redesign to increase efficacy and reduce side effects of these important drugs,” Taylor said.
Taylor’s findings were published in the Nature Publishing Group’s journal Scientific Reports in May.
“Ever since I started at Wesleyan one of my driving focuses has been the search for new antibacterial compounds – the search for new drugs, and new targets for those compounds. There have been a lot of tried-and-true targets that the pharmaceutical industry has exploited over the years, but antibiotic resistance has gotten more and more prevalent,” Taylor said. “It’s really important that we figure out new targets and new strategies to kill these bacteria.”
Taylor described an enzyme as like a machine with small cavities where chemistry can take place. Inhibitors, which are often antibiotics, work by binding on to cavities located on a bacterial enzyme, preventing vital functioning in the bacteria. If the vital function is prevented from happening, the bacteria will die.
“If you can imagine, the little inhibitor (provided by the antibiotic) fits precisely in that little pocket of the metabolic machine. If the bacteria changes the code for making that machine, thus changing the size of the pocket, the inhibitor might not work as effectively. This is how resistance develops,” she said.
Taylor focuses her research on Gram-negative bacteria drug discovery. “Gram-negatives are prevalent and they’re challenging,” Taylor said. “Hundreds of people die every year from simple infections in the United States … It says we don’t have the right tools yet.”
The target protein an antibiotic is designed to bind to in Gram-negative bacteria is hidden behind two membranes, which makes that much harder for the drugs to get to the target and therefore to be effective.
Most antibiotics were developed in the 1950s through 1970s and our understanding of how they work has not much evolved since then, Taylor said. In addition, the ubiquity of antibiotics in our food supplies has rendered them less effective against bacteria.
Using modern tools like detailed kinetic analyses, circular dichroism spectroscopy, intrinsic tryptophan fluorescence, computational docking, and molecular dynamics simulation, Taylor and her team were able to identify a new protein that these antibiotics bind to with high affinity. By suggesting that antibiotics target a different protein in a bacteria, Taylor is calling into question long accepted dogma.
“While aminoglycosides have long been described as potent antibiotics targeting bacterial ribosomes’ protein synthesis, leading to disruption of the stability of bacterial cell membranes, more recently researchers have shown that they only modestly impact protein production,” according to the abstract of Taylor’s paper.
Taylor believes that if aminoglycoside antibiotics work by targeting a different protein (called Heptosyltransferase I or HepI), then she and others would be able to modify the structure of the aminoglycosides to allow them to be even more effective – to be more strongly attracted to HepI. “This could open a whole new avenue for evaluating how to design these inhibitors to make them more potent,” Taylor said.
The process of reexamining what would appear to be settled pharmaceutical dogma is a long one. Taylor expects it could take over a decade of research to definitively establish a new way of thinking, and to develop and test new molecules based upon her discovery. However, if this research can lead to more effective antibiotics, this could not only change pharmaceutical industry practices, but also what medicines doctors prescribe to their patients.
“When I was young, my dad wanted me to be a doctor like him. I remember saying to him, I want to find my own path. If I am a physician, I will impact a small subset of people. If I am a researcher and I discover new drugs, I can impact millions,” Taylor said.