Die, Bacteria!

The global rise in antibiotic resistance is a growing threat to public health, yet efforts to develop new antibiotics are not keeping pace with the growth in microbial resistance.

Now researchers at MIT, the Broad Institute at MIT and Harvard, and Harvard University have engineered particles known as phagemids, which can produce toxins that are deadly to targeted bacteria.

Bacteriophages—viruses that infect and kill bacteria—have been used for many years to treat infection in the former Soviet Union. Unlike traditional broad-spectrum antibiotics, these viruses target specific bacteria without harming the body’s normal microflora.

But they can also cause harmful side effects, says James Collins, a professor of medical engineering, who led the research. “Bacteriophages kill bacteria by lysing the cell, or causing it to burst,” he says. “But this can lead to the release of nasty toxins from the cell.” That can cause sepsis or even death.

Collins and colleagues had already engineered bacteriophages to express proteins that did not burst the cells but instead increased the effectiveness of antibiotics delivered at the same time. Building on that work, they used synthetic biology techniques to develop phagemids. These particles infect bacteria with small DNA molecules known as plasmids, which are able to replicate independently inside a host cell. Once inside the cell, the plasmids produce antimicrobial peptides and bacterial toxins that disrupt cellular processes such as bacterial replication, causing the cell to die without bursting open.

The phagemids will only infect a specific species of bacteria, resulting in a highly targeted system. “You can use this to kill off very specific species of bacteria as part of an infection therapy, while sparing the rest of the microbiome,” says Collins.