Re-engineered Antibodies Kill Bacteria Directly
These antibodies use a clever trick to slip deep into a bacteria’s outer membrane, where they can do real damage.
A microscope image of a bacterium that has been treated with a re-engineered antibody that can slip into its outer membrane and target a key structural protein, making the membrane unstable.
Antibodies have a hard time getting past the surface of a bacterium’s outer membrane, so they usually need helpers to kill them. But a new method, described by a team from The University of Texas at Austin in the journal PNAS, coats antibodies with a positive charge, allowing them to slip deep into the outer membrane, find a key structural protein and burst open the bacterium.
The research team was led by Bryan Davies, professor of molecular biosciences and Angela O’Donnell, a graduate student.
On the left: healthy, intact bacteria. On the right: a bacterium that was treated with the new antibodies has burst open, spilling its contents.
Antibodies developed with this new method have been shown effective in cell cultures and are non-toxic to human blood cells, but many challenges remain to develop an effective clinical treatment. For example, it currently takes a large dose to kill bacteria and the biological systems they use to manufacture the antibodies have low yield. Any such drug will also need to be proven effective and safe in animal models before human clinical trials.
To develop a candidate antibody, the researchers first engineered E. coli bacteria to display over 100,000 antibody variants (using a technology called SLAY) and tested them to see which, if any, had antibacterial properties when interacting with bacteria whose membranes had already been compromised. They found a couple of candidates and determined which bacterial targets they bound to. When they tested these antibody candidates against healthy bacterial cultures, they didn’t work. Surmising that it was because the antibodies weren’t penetrating the bacterial membranes, they added a positive charge to the antibodies, enabling them to kill the bacteria.
Read more in PNAS: www.pnas.org/doi/10.1073/pnas.2509305122
