Maryland Initiative Against Superbugs

Antibiotic-resistant bacterial ‘superbugs’ are a global health threat that cause 1.25 million deaths every year. Unfortunately, this crisis is only deepening, driven by the persistent misuse of antibiotics in human medicine and agriculture and the shrinking pipeline of new antibiotics, with projections indicating that annual deaths due to drug-resistant infections will reach 2 million by 2050. The National Institutes of Health (NIH) highlighted phage therapy as a key investment priority as part of a broad portfolio of alternative strategies to confront drug-resistant superbugs. Bacteriophage (phage) are viruses that infect and kill bacteria. Unlike broad spectrum antibiotics, phage are highly specific, and can be selected and engineered to target multi-drug-resistant (MDR) superbugs rather than the good microbes that live inside and on us. However, phage therapy can often fail because therapeutic phage do not target the particular strain that causes a life-threatening infection or because the superbugs evolve resistance to phage during therapy.

The long-term aim of this project is to advance the clinical translation of phage therapies and contribute to the global fight against drug-resistant superbugs. The team will establish a phage discovery pipeline to identify and evaluate phage therapeutic candidates for targeted clearance of MDR pathogens, leveraging the combined expertise of researchers that span computational modeling, product engineering, and experimental validation of therapeutic potential on clinically relevant bacterial strains. The team will first leverage a novel approach to use large sequence databases and publicly available metagenomic datasets to identify candidate sequences of therapeutic phages and phage products against four types of pathogens that contribute to a majority of infection. In parallel, the team will use a wet lab discovery pipeline to isolate and enrich phages from Maryland wastewater facilities and farm water samples. These parallel approaches will provide phage biology training to students. The team will also leverage AI foundation models, eco-evolutionary models, and protein engineering to enhance the range, efficacy, and evolutionary robustness of phage therapeutic candidates. Lastly, the researchers will test and deploy novel phage and phage products against clinical isolates of MDR bacteria.

This project will advance phagetherapies as a viable option for treating increasingly common drug-resistant infections. This project will develop a bioinformatic pipeline and model-based approaches to discover and improve therapeutic efficacy of phages and phage products to reduce treatment failure. Moreover, the development of these therapies will serve as rapid, customizable and precision based treatments that will reduce patient harm by solely targeting and destroying the pathogen without alteration of the host microbiome or its normal biological functions. The team will build a sustainable infrastructure that connects expertise to take on one of the most significant human health problems of this century. It will also accelerate the integration of computational and experimental approaches to advance the understanding of and application of phage for innovative therapies.