Drug-Resistant Infections

Sukrit Silas is focused on expanding our understanding of the enormous genetic diversity of bacteriophages. He and his team are systematically screening tens of thousands of phage genes in diverse bacterial strains to define what part of the phage is lethal to bacteria and to identify those with the best potential to counter today’s top antimicrobial threats. They are searching for viral components that can be harnessed or engineered to overcome bacterial defenses and restore the ability to kill antibiotic-resistant pathogens.

By pinpointing common antivirus mechanisms in bacteria, the lab is painting a comprehensive picture of the entire defense architecture that phages encounter when infecting cells. The scientists are combining this information with AI tools to engineer phage cocktails that can be used as reliable therapeutic agents in the fight against drug-resistant bacteria that no longer respond to standard treatments.

A team led by Sukrit Silas is studying the most widespread antiviral defense in bacteria, a mechanism known as the “restriction modification” system. This defense system detects DNA from an invading phage and cuts it into pieces before the phage can take over the cell.

They have shown just how far bacteria will go to survive infection. When phages try to bypass the cell’s defenses, some bacteria respond with an extreme last resort: they activate internal systems that cause the infected cell to self-destruct. This prevents the virus from taking over and spreading to neighboring bacteria.

Understanding these hidden defense strategies reveals new weaknesses in phages, which could be exploited to design better phage-based or other antimicrobial therapies. Ultimately, the work helps scientists uncover new ways to fight drug-resistant infections by turning bacterial-virus interactions into potential treatment tools.

While thousands of phages exist, using them as treatments to fight specific bacteria has so far proven to be challenging. Seth Shipman and his team are developing a technology that lets them edit the genomes of phages in a streamlined and highly effective way, giving them the ability to engineer new phages and study how the viruses can be used to target specific bacteria.

The new system speeds up the process of editing phage genomes, allowing scientists to rapidly create and test many different engineered versions. This could help identify phages that are better at targeting and killing dangerous, resistant bacteria. By making phage design more efficient and scalable, the technology also brings phage therapy closer to becoming a practical treatment option when antibiotics fail.

Seth Shipman’s group created a useful system to edit DNA in 15 species of bacteria, spanning three major branches of the bacterial family tree. This will make it easier to study drug-resistant bacteria, which have been difficult to manipulate with older tools that only work in limited organisms.

The new system adapts a natural bacterial defense mechanism called retrons to make precise genetic changes in bacteria. This gives scientists a faster, more flexible way to investigate how harmful bacteria function and how they become resistant to antibiotics. Ultimately, the technology could accelerate the development of new treatments by making it easier to redesign bacteria, test potential therapies, and identify new vulnerabilities in drug-resistant pathogens.

Gladstone has received an initial $2 million award from the National Institute of Allergy and Infectious Diseases (NIAID), with the potential for up to $10 million over five years, to establish the Center for PhAIge Therapy. The center brings together researchers to develop engineered phage treatments for antibiotic-resistant bacterial infections and accelerate their path toward clinical use.