Recent research by Erika A. Taylor, an associate professor of chemistry, suggests that the way scientists have long believed that certain antibiotics used to treat bacterial infections work may 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, Salmonellaand v. choleraamong others.
The research stakes are real, Taylor explained. Better antibiotics would prevent unnecessary deaths E.coli, Salmonella and other Gram-negative bacteria. Relatively simple treatments, such as those for urinary tract infections, would be more effective and improve people’s quality of life.
“I’m excited about the prospect of rewriting history on how these antibiotics work, because new insights into how these drugs work could allow their redesign to increase efficacy and reduce side effects of these important drugs,” Taylor said.
Taylor’s findings were published in Nature Publishing Group’s Scientific Reports journal in May.
“Since I started at Wesleyan, one of my main goals 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 proven targets that the pharmaceutical industry has exploited over the years, but antibiotic resistance has become more and more prevalent,” Taylor said. “It’s really important that we find new targets and new strategies to kill these bacteria.”
Taylor described an enzyme as a machine with small cavities where chemistry can take place. Inhibitors, which are often antibiotics, work by binding to the cavities on a bacterial enzyme, preventing the bacteria from functioning vitally. If vital function is prevented from occurring, the bacteria will die.
“If you can imagine, the little inhibitor (provided by the antibiotic) fits precisely into that little pocket of the metabolic machine. If the bacteria changes the manufacturing code of that machine, thereby changing the size of the pocket, the “inhibitor might not work as effectively. That’s how resistance develops,” she said.
Taylor focuses her research on drug discovery against Gram-negative bacteria. “Gram-negatives are prevalent and they’re difficult,” Taylor said. “Hundreds of people die every year from simple infections in the United States…That means we don’t have the right tools yet.”
The target protein that an antibiotic is designed to bind to in Gram-negative bacteria is hidden behind two membranes, making it that much harder for drugs to hit the target and therefore be effective.
Most antibiotics were developed in the 1950s to 1970s, and our understanding of how they work hasn’t changed much since then, Taylor said. Additionally, the ubiquity of antibiotics in our food supply has made them less effective against bacteria.
Using modern tools such as detailed kinetic analyses, circular dichroism spectroscopy, intrinsic tryptophan fluorescence, computational docking, and molecular dynamics simulation, Taylor and his team were able to identify a novel protein to which these antibiotics bind with high affinity. By suggesting that antibiotics target a different protein in a bacterium, Taylor challenges long-held dogma.
“While aminoglycosides have long been described as potent antibiotics targeting bacterial ribosome protein synthesis, leading to disruption of the stability of bacterial cell membranes, more recently researchers have shown that they only impact modest on protein production,” according to Taylor’s abstract of the paper.
Taylor thinks that if aminoglycoside antibiotics work by targeting a different protein (called heptosyltransferase I or HepI), then she and others would be able to change the structure of aminoglycosides to allow them to be even more effective – to be more strongly attracted to HepI. “This could open up a whole new avenue for evaluating how to design these inhibitors to make them more potent,” Taylor said.
The process of re-examining what appears to be established pharmaceutical dogma is a long one. Taylor expects it will take more than a decade of research to definitively establish a new way of thinking and to develop and test new molecules based on his discovery. However, if this research can lead to more effective antibiotics, it could not only change the practices of the pharmaceutical industry, but also the drugs doctors prescribe to their patients.
“When I was young, my dad wanted me to be a doctor like him. I remember telling him, I want to find my own path. If I’m a doctor, I will impact a small subset of people. If I’m a researcher and discover new drugs, I can impact millions of people,” Taylor said.