Daniel Reker and Katherine Franz Receive Wellcome Leap Funding to Develop Safer Antibiotics

Daniel Reker, an assistant professor of Biomedical Engineering, and Katherine J. Franz, the James B. Duke Distinguished Professor of Chemistry, were awarded funding through Wellcome Leap’s Focused Antibiotics program to develop a new approach to treating bacterial infections—one designed to spare the gut microbiome, while still effectively eliminating disease-causing bacteria.

Wellcome Leap is a U.S. nonprofit founded by the Wellcome Trust to accelerate breakthroughs in human health . It represents a new model for research—designed to be fast, agile, and networked across disciplines, organizations, and countries. The Duke team is one of only 16 research teams from around the world selected to participate in the Focused Antibiotics program, which will provide up to $50 million in total funding to develop new approaches to combat antibiotic resistance by reducing the unintended effects of antibiotic treatment.

Antibiotics are among modern medicine’s most important tools. Every year, roughly one in three people worldwide takes antibiotics to treat infections ranging from urinary tract infections and skin infections to life-threatening illnesses such as pneumonia. In hospitals, these drugs are indispensable, protecting patients undergoing surgery, chemotherapy and organ transplantation from potentially deadly infections.

But the effectiveness of antibiotics is increasingly threatened by the rise of antibiotic resistance. The consequences are already devastating. In 2021 alone, antibiotic-resistant infections were directly responsible for more than 1.14 million deaths worldwide, and that toll is projected to reach as many as 8 million deaths annually by 2050.

One factor driving this growing threat is the way antibiotics are delivered. Most infections are confined to a specific organ or area of the body, yet antibiotics are typically administered systemically through oral tablets or injections, exposing the entire body to the drug. This widespread exposure can have unintended consequences in the gut, where antibiotics kill not only harmful bacteria but also susceptible members of the healthy microbiome. Resistant bacteria are more likely to survive, allowing them to multiply and accumulate resistance genes within the gut. And those genes don’t necessarily stay put. Bacteria can exchange genetic material, potentially passing resistance to pathogens and making future infections harder––or sometimes impossible––to treat.

Rather than searching for entirely new antibiotics, the Duke team aims to redesign medicines that are already clinically established, potentially preserving their effectiveness while eliminating an important source of collateral damage. Their approach combines artificial intelligence with a class of drugs known as prodrugs––medications that are administered in an inactive form and then converted inside the body into an active drug when it reaches the desired tissue––like an automated “on-switch” for medicines.

“We will use AI to figure out how to modify currently available antibiotics so that they don’t affect commensal gut microbes anymore, but instead activate once they hit the site of infection,” said Reker. “This would also ideally reduce side effects from antibiotic use, which can range from gastrointestinal distress to an increased vulnerability to other infections since the protection provided by the microbiome has been decimated.” 

“We will use AI to figure out how to modify currently available antibiotics so that they don’t affect commensal gut microbes anymore, but instead activate once they hit the site of infection. This would also ideally reduce side effects from antibiotic use, which can range from gastrointestinal distress to an increased vulnerability to other infections since the protection provided by the microbiome has been decimated.”

Daniel Reker, Assistant Professor of BME

The strategy builds on complementary expertise from the Reker and Franz labs. Reker’s group develops AI and machine-learning approaches for designing and optimizing drug molecules, while Franz’s lab has developed chemical structures that can be activated in the presence of pathogens. Together, the researchers will use these capabilities to identify chemical mechanisms that can distinguish an infection from the surrounding tissues and microbiome, then incorporate those mechanisms into new antibiotic therapies.

“We don’t just want to carpet bomb an infection, we want to see what kinds of chemical mechanisms are specific to that local environment or pathogen that we can use to trigger molecules,” said Franz. “Partnering with the Reker lab and their AI and machine learning platforms help us expand our design space and look at the problem more creatively.” 

We don’t just want to carpet bomb an infection, we want to see what kinds of chemical mechanisms are specific to that local environment or pathogen that we can use to trigger molecules. Partnering with the Reker lab and their AI and machine learning platforms help us expand our design space and look at the problem more creatively.

Katherine Franz, James B. Duke Distinguished Professor

Successfully deploying microbiome-sparing antibiotics as first-line treatments for common infections could reduce antibiotic-driven resistant infections by as much as 40%, potentially preventing more than 100 million resistant infections over the next decade. This is the overall goal of the Focused Antibiotics program.

“We’ve already developed AI platforms to re-design antibiotics, and we’re thrilled we will be able to further enhance this platform and deploy it to create hopefully several new drug leads,” said Reker. “Antibiotics resistance is a scary problem, and we’re grateful our work was recognized as a potential part of the solution.”