When a bacterial infection no longer responds to antibiotics, doctors have few treatment options. Phage viruses that naturally infect and kill bacteria have long intrigued clinicians as potential weapons against these infections. But converting these tiny bacteria hunters into drugs is slow and unreliable.
New efforts leveraging engineering and artificial intelligence could change this.
The Gladstone Institute has received an initial grant of $2 million from the National Institute of Allergy and Infectious Diseases (NIAID), with additional funding totaling up to $10 million available over the planned five-year project period. This grant will establish the PhAIge Therapies Center, a research center to develop new phage-based treatments for antibiotic-resistant bacterial infections.
The five-year grant will make Gladstone one of three institutions across the country selected to lead this collaborative effort. ESKAPE The new Center for the Advancement of Phage Therapies to Combat Pathogens (CAPT-CEP) will collaborate to advance the therapeutic use of phages.
The PhAIge Therapy Center will be overseen by Gladstone researcher Dr. Seth Shipman, with a multidisciplinary team of other Gladstone scientists leading the project and core components.
Phages have the potential to treat drug-resistant infections, but for patients to benefit from that potential, we need to be able to predict which phages to use on which patients and design phages that are more effective than what we currently have. That is the purpose of this center. ”
Dr. Seth Shipman, Agent Gladstone
Tackling serious threats to modern medicine
Each year, approximately 5 million deaths worldwide are related to antibiotic-resistant infections.
People with weakened immune systems, such as cancer patients receiving immunotherapy, are particularly vulnerable because they rely heavily on effective antibiotics. However, antibiotic resistance is no longer limited to high-risk patients and is now impacting the broader hospital population.
Among the main causes of these deaths is a major hospital “superbug” called the ESKAPE pathogen.Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosaand enterobacter seed.
These bacterial species are on the World Health Organization’s list of priority pathogens. They are considered a serious threat to modern medicine because they not only resist drugs, but also replace their defense mechanisms and quickly adapt when exposed to new antibiotics.
Phages have evolved the ability to kill bacteria in a distinct and targeted manner and are therefore of increasing interest as potential weapons against ESKAPE pathogens and other antibiotic-resistant infections.
Despite promising results in individual patients so far, phage therapy remains difficult to use on a large scale, in part because it requires so much trial and error for each patient.
The new PhAIge Therapeutic Center will build the preclinical tools and models needed to overcome this obstacle and make phages a more reliable infectious disease treatment.
Gladstone scientists have developed an AI tool to predict which phages will work against particular bacterial strains, but the model lacks the right data to make its predictions accurate. The researchers therefore plan to conduct large-scale experiments using engineered phages and bacteria to better understand step-by-step how bacteria are killed.
“Our center’s goal is to generate unprecedented amounts of data and train AI models to identify the right phages for every patient infection,” Shipman says.
Deploy phages against drug-resistant pathogens
Shipman’s lab has already developed tools to precisely edit phage genomes in highly effective ways, making it possible to engineer new phages.
The PhAIge Therapies Center will enable the team to build on that technology and develop new tools to accelerate research into how best to optimize and deploy phages against ESKAPE pathogens.
They plan to build a high-throughput assay to measure how individual parts of the phage contribute to its activity against bacteria. This project will ultimately generate the data needed to rationally design and select phages that are effective against bacteria. Klebsiella pneumoniae.
In the medical field, Klebsiella pneumoniae It can cause serious infections, including pneumonia, bloodstream infections, and meningitis, among patients on ventilators and intravenous catheters. These bacteria are becoming increasingly resistant even to antibiotics, the last line of defense against bacterial infections, and are responsible for more than 600,000 deaths each year.
Parallel to Shipman’s research, Gladstone investigator Dr. Skrit Silas investigated how Klebsiella pneumoniae Strains differ in their susceptibility to phages, with the aim of identifying the combination of phages most likely to work against a particular strain.
Both projects are driven by close collaboration with Dr. Katie Pollard, Director of the Gladstone Institute for Data Science and Biotechnology, and Melanie Ott, MD, Director of the Gladstone Institute for Infectious Diseases.
Pollard will lead the development of new algorithms to predict the compatibility of phage-bacteria pairs and optimize natural phages as medicines. Ott’s team plans to use human lung organoids, which more closely mimic human tissue than traditional animal models, to study how the body’s environment influences phage behavior and treatment outcomes, which cannot be captured in traditional laboratory models.
“What excites me about this series of projects is that we are building a system where data and AI build on each other with each iteration,” Shipman said. “We’re not just studying phages using the same methods as in the past; we’re creating an infrastructure to reasonably predict how phages can be used successfully in the future.”
In addition to the Gladstone PhAIge Treatment Center, the CAPT-CEP network will also support Stanford University’s Phage Medicine Center, which will focus on phage delivery to the lungs, and the University of Pittsburgh’s Phage Therapy Acceleration Pit Center, which will develop assays to design and administer phage cocktails for patients. The three centers will share assays, materials, and data.
