Arming antibiotics with a vaccination-like immune response

11 July 2018

Angus Liu / FiercePharma

Harnessing the power of the body’s immune system has already proven to be effective in treating cancer. Scientists at Lehigh University are now borrowing that idea to power up existing antibiotics’ ability to attack drug-resistant bacteria.

A team led by Marcos Pires, Ph.D., a Lehigh associate professor of biochemistry, grafted antigenic epitopes—parts of pathogens that can be recognized by the immune system—onto an old antibiotic called colistin, creating what they call “bacterial immunotherapy” or “immunobiotics.” As described in a paper published in the journal Cell Chemical Biology, the compound killed a large number of E. Coli bacteria in human serum.

Pires’ team had previously labeled the surface of Gram-positive bacteria with antigenic epitopes to induce an antibody response, Pires told FierceBiotechResearch. They synthesized D-amino acids with an antigen that draws attack from human antibodies, so that when bacteria incorporate these lab-produced building blocks to construct their outer layer, they become targets for destruction.

But Gram-negative bacteria like E. coli and P. aeruginosa are a different story. Because the cell membranes of Gram-negative bacteria have an extra layer of protection, they are particularly hard to destroy. To make it worse, these bacteria constantly evolve, rendering antibiotics inefficient.

For example, amid the global crisis of antibiotic resistance in 2016, the U.S. discovered its first human E. coli infection case with mcr-1 gene, which makes E. coli resistant to colistin, a last-resort antibiotic.

Some scientists have been trying to tackle the extra protective layer on Gram-negative bacteria. A Genentech team led by Steven Rutherford, for example, is also using an immunotherapy approach to fight superbugs. In their recent research, they recruited a monoclonal antibody to target BamA, an enzyme that builds the outer wall of Gram-negative bacteria.

In contrast, Pires’ team assembles its therapy by combining polymyxin B—a colistin that inherently attaches to the lipid A in the surface of Gram-negative pathogens—with antigenic epitopes that attract antibodies. With the help of Lehigh Prof. Wonpil Im’s lab, which uses computational biophysics to understand antibiotics’ interaction with bacterial membranes, the team was also able to model how the bacteria’s surface could affect immune system activation.

The result? “[A] compound that both directly kills bacteria and at the same time induces an immune response,” said Pires in a statement. “With this one-two punch against these difficult to kill bacteria, we believe there is great potential for in vivo testing to evaluate them further," said Pires.

The team put their immunotherapeutic compounds in real human serum with a panel of Gram-negative pathogens, including E. coli, and saw a significant decrease in the number of live bacteria. They also showed that the therapy can label the surface of Gram-negative bacteria in a live host.

Next up, Pires’ group plans to expand the in vivo studies to complex animals. And in addition to stimulating the body’s own immune system to attack the bacteria, the group is thinking about introducing complementary antibodies not naturally found in the body—like what the Genentech team is doing—to achieve better results, Pires said.

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