Bacterial Biodiversity and the Potential for Phage Resistance

Natural evolution versus laboratory evolution—these subtle changes could make the biggest of differences when it comes to antimicrobial resistance. Where do you think a more resistant bacteria would evolve from? Many might think the lab, but a new study out of the University of Exeter is pointing to the natural environment as a source for microbial resistance to phage therapy.

Phage therapy has been discussed as a new tactic against resistant infections and a dwindling antibiotic pipeline. With an estimated 2 million antibiotic-resistant infections occurring each year in the United States, it’s not surprising that at a global level, we’re working to find new strategies.

Unlike creating novel antibiotics, phage therapy utilizes bacterial viruses (phages) to help infect and lyse the bacteria causing the infection. In fact, this approach was utilized for a 15-year-old patient battling a disseminated resistant infection. The patient was given the experimental treatment after acquiring a resistant infection with Mycobacterium abscessus following a lung transplant.

It is common for patients with cystic fibrosis to acquire drug-resistant lung infections and, in many cases, these can lead to death. The investigators tried a 3-phage intravenous cocktail that was developed by genome engineering and forward genetics. The therapy worked and has shed light on the potential for phage therapy.

Unfortunately, the efficacy of phage therapy is now being called into question by a new study out of the University of Exeter. When examining the bacterium Pseudomonas aeruginosa and its development of resistance to phages, they found that when such evolution happened in the lab, the bacteria also lost a receptor in which the phage attached itself to.

In a natural environment though, the resistance was a product of an immune reaction via a CRISPR-based resistance that didn’t impact the bacteria’s virulence. Meaning that when the surface receptor is lost, the bacteria become less competitive compared to other bacteria, which impacts their efficacy and overall functionality in the lab environment.

Lead author Ellinor Alseth, PhD, of the University of Exeter’s Environment and Sustainability Institute, noted that “with the CRISPR evolutionary route, the bacteria maintain their level of virulence rather than becoming less virulent."

CRISPR-Cas adaptive immune systems are present in roughly half of bacteria genes and help provide them with a memory “by inserting short DNA sequences from phage and other parasitic DNA elements into CRISPR loci on the host genome.” The investigators found that when Pseudomonas aeruginosa and the phage DMS3vir were in the presence of other pathogens (like they would normally be in the environment), that competitive aspect became critical and ultimately meant the CRISPR-based resistance would prove more efficacious.

Perhaps this indicates that the “quality” of resistance bacteria like Pseudomonas aeruginosa acquire in a lab environment and without the competitive nature of other pathogens, truly makes or breaks the capabilities. Understanding those dynamics that impact an organism like Pseudomonas aeruginosa, especially with the developing phage therapies, is a critical component in the quest to combat multidrug-resistant organisms. In many ways, this study will help guide predictive modeling and efforts to enhance the efficacy and utility of phage therapy.