DNA-Antibody Hybrid Molecule Shown to Be Effective Antibacterial Agent

A hybrid molecule comprising an aptamer attached to a trisaccharide terminating with alpha-gal (N-acetyl-glucosamine) was shown in a proof-of-principle study to be an effective antibacterial agent.

Aptamers are nucleic acid species that have been engineered through repeated rounds of in vitro selection to bind to various molecular targets such as small molecules, proteins, and nucleic acids. Aptamers are useful in biotechnological and therapeutic applications as they offer molecular recognition properties that rival that of antibodies. In addition to their discriminate recognition, aptamers offer advantages over antibodies, as they can be engineered completely in a test tube, are readily produced by chemical synthesis, possess desirable storage properties, and elicit little or no immunogenicity in therapeutic applications. Relative to monoclonal antibodies, aptamers are small, stable, and non-immunogenic.

Humans do not express the galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl-glucosamine (alpha-Gal) epitope. However, as a result of exposure to alpha-Gal in the environment, humans develop a large quantity of circulating antibodies that are specific for this trisaccharide.

Investigators at the University of California, San Diego (USA) developed a DNA aptamer that was able to bind to group A Streptococcus (GAS) bacteria by recognition of a conserved region of the surface-anchored M protein. To the 5′ end of this aptamer they conjugated an alpha-Gal epitope. This hybrid molecule was termed an "alphamer." The intent was that the aptamer segment of the alphamer would attach the molecule to the target bacterium while the alpha-Gal fragment would bind to the body's normally circulating anti-alpha-Gal antibodies.

In a paper published in the May 5, 2015, online edition of the Journal of Molecular Medicine the investigators showed that an anti-GAS alphamer could recruit anti-Gal antibodies to the streptococcal surface in an alpha-Gal-specific manner, elicit uptake and killing of the bacteria by human phagocytes, and slow growth of invasive GAS organisms in human whole blood.

These results constituted the first in vitro proof of concept that alphamers had the potential to redirect preexisting antibodies to bacteria in a specific manner and trigger an immediate antibacterial immune response.

"We are picturing a future in which doctors have a case full of pathogen-specific alphamers at their disposal," said senior author Dr. Victor Nizet, professor of pediatrics and pharmacy at the University of California, San Diego. "They see an infected patient, identify the causative bacteria, and pull out the appropriate alphamer to instantly enlist the support of the immune system in curing the infection."

The alphamer concept was attributed to contributing author Dr. Kary Mullis, winner of the 1993 Nobel Prize for chemistry for his invention of the polymerase chain reaction (PCR), technique. Dr. Mullis has established a biotech company, Altermune Technologies (Irvine, CA, USA), to develop alphamers into commercially viable therapeutic tools.

Related Links:
University of California, San Diego
Altermune Technologies