How quickly engineered viruses could fight drug-resistant bacteria

Naturally occurring viruses called bacteriophages are known to kill bacteria. But because there are so many of them and each of the viruses can only infect very specific bacterial strains, finding and optimizing the right phage cocktail to fight a bacterial disease can be time-consuming and costly.

Biological engineers at the Massachusetts Institute of Technology (MIT) have found a way to rapidly turn phages into tailor-made weapons against particular strains of Escherichia coli. They did it by manipulating the structure of the viruses’ tail fibers. The engineered phages can kill bacteria subtypes that had developed resistance against natural phages, the researchers reported in the journal Cell.

An MIT team led by associate engineering professor Timothy Lu, M.D., Ph.D., previously developed a synthetic biology strategy to modulate phages from the T7 family, which can naturally kill E. coli. By genetically engineering the tail fiber—which phages use to latch onto their targets—the researchers generated new phages that target other bacteria.

While that method worked well, the researchers wanted to speed up the process. They knew that the tail fiber protein is made up of structures called beta sheets that are connected by loops. So, Lu and colleagues decided to systematically change just the amino acids that form the loops.

“We identified regions that we thought would have minimal effect on the protein structure, but would be able to change its binding interaction with the bacteria,” said Kevin Yehl, a postdoctoral research associate and the study’s co-first author, in a statement.

The researchers made phages with about 10 million different tail fibers. They found some of the doctored phages could kill strains of E. coli with mutated or missing LPS receptors, which the bacteria developed to fight existing phages.

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Engineered phages are among several technologies being investigated as potential solutions to the problem of antibiotics resistance. In another study study published this week, scientists at Imperial College London focused on a system that some bacteria use against other bacteria in their fight for resources.

The team found Pseudomonas aeruginosa uses a “toxic arrowhead” called VgrG2b to target a rival bacterium’s cell envelope, carrying a toxin called a metallopeptidase, which the team showed is an enzyme that cuts up proteins and causes the cell to eventually explode.

“The impact of VgrG2b on target cells mimics the action of beta-lactam antibiotics. Yet it is clear that its mode of action is different,” said the study’s first author Thomas Wood in a statement. “By further understanding and characterizing the molecular targets of VgrG2b, and how the toxin works, this research would support the design of new antibiotics.” The research was published in Cell Reports.

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Phages, meanwhile, continue to gain steam in the research community. Locus Biosciences, a FierceBiotech 2019 Fierce 15 winner, uses a high-throughput phage discovery platform to identify the right combination of phages for different bacterial species and powers them up with a CRISPR-Cas3 payload that can chew up the DNA pathogens rely on to survive. The biotech recently penned a deal worth up to $818 million with Johnson & Johnson.

Lu, Yehl and colleagues at MIT now plan to repurpose their engineered viral “scaffold” against other resistance mechanisms used by E. coli as well as other disease-causing bacteria.