At the forefront of the fight against antibiotic resistance, a team of scientists led by St. Jude Children's Research Hospital researchers have developed a new weapon. The second-generation antibiotic shows early effectiveness against common bacterial infections that have the potential to develop antibiotic resistance and pose a serious health threat to children and adults.
To achieve this result the team changed the chemical structure of an old antibiotic named spectinomycin. St. Jude researchers have taken this approach before successfully; this study describes the second time in recent years that St. Jude scientists have created promising antibiotics in this way. Spectinomycin is safe, but this 1960s antibiotic is weak, making it a good candidate for enhancement.
The team built on years of research to create new, more potent "analogs" of spectinomycin. The team's results show that analog 1950 is as effective at protecting mice from Streptococcus pneumonia-a strain which is often lethal-as the antibiotic ampicillin. These bacteria cause pneumococcal infections, including meningitis, pneumonia, sepsis, and the ear infection otitis media in humans.
In the laboratory the team was able to prevent strains of the pneumococcal bacteria resistant to commonly used antibiotics from growing using the spectinomycin analogs. The analogs were also more effective against bacteria responsible for most cases of Legionnaires' disease, chlamydia, gonorrhea, Haemophilus influenza, and Moraxella catarrhalis.
"The growing problem of drug-resistant bacteria has created an urgent need for new antibiotics that use novel mechanisms to treat adults and children worldwide. Immune-compromised St. Jude patients undergoing treatment for other indications, as well as adults and children are particularly at risk from these types of secondary infections," says Richard Lee of the St. Jude Department of Chemical Biology and Therapeutics, author of the study.
According to the Centers for Disease Control and Prevention (CDC), drug-resistant bacteria sicken about two million people in the US each year and cause around 23,000 deaths. Antibiotic resistance has been called a security threat by the Obama administration, and combating it is a national priority.
Lee's method has included the exhaustive review of medical literature on antibiotics from 20 or 30 years ago-a time when resistant bacteria were rare and antibiotics were plentiful. Lee searches for good candidate antibacterials, especially natural products like spectinomycin. His goal is to find products that can be enhanced for improved potency using structure-based design to re-engineer them. This process also helps Lee create new analogs that avoid antibiotic resistance and reduce the risk of side effects.
In 2014, Lee and his team created spectinamides, a new class of antibiotics designed specifically to treat drug-resistant tuberculosis (TB) with this approach. The drugs accumulate within the cell and inhibit protein synthesis leading to TB cell death using a novel mechanism; they are still in development.
In this latest investigation, the team again used structure-based design to map and re-engineer the binding process between spectinomycin and the ribosomes of clinically important bacteria. This recent work focuses on generating compounds that are effective against a broader spectrum of disease-causing bacteria.
1980s research with the Upjohn Co., later part of Pfizer, formed some of the basis for the St. Jude research. The Upjohn team showed that the potency of spectinomycin could be improved by chemically modifying its core. The project was abandoned later in favor of research on other antibiotics.
It's the time since then which has made all of the difference; we now know the structure of the ribosome. Researchers also now have technological advances on their side, allowing them to use a 3-D model of spectinomycin bound to bacterial ribosomes at the atomic level. The St. Jude team used Upjohn's modification chemistry to produce 20 new versions of spectinomycin, all structure-guided, including analog 1950 and three others that are the focus of the study report.
"The re-engineered spectinomycin has a new hook it uses to enter a broad range of bacteria, bind to the ribosome and block protein synthesis," Lee says. He speculated that the redesign might also give the medicine a better shot at success by preventing efflux, a process in which bacteria pump out the drug like you'd pump water from a leaking ship.
Laboratory results indicate that the spectinomycin analogs were unlikely to interfere with other medications or cause serious side effects. The St. Jude continues its work on the analogs.
The findings appeared this week in the scientific journal Science Translational Medicine. Team members are also from the University of Tennessee Health Science Center in Memphis and the University of Zurich.
