‘Homing beacon’ for pathogens

The researchers involved tell DDNews that their study potentially opens up a completely new approach to fighting multidrug resistant bacteria and infectious diseases more generally.

“This is the first essential proof of principle of an entirely novel approach to infectious disease therapy: that natural antibodies present in our body can be redirected to target a pathogen by using the Alphamer as a linker,” Victor Nizet, professor of pediatrics and pharmacy at UC San Diego, tells DDNews. Nizet, whose laboratory studies how pathogens interact with the human immune system, participated in the research that resulted in a study published in Journal of Molecular Medicine.

The homing beacon used by researchers contains two ends with distinct components. One end is made up of a DNA aptamer, a small piece of DNA that can be selected from a pool of billions of candidates based on its ability to bind tightly to a particular target. In this test case, the aptamer specifically targeted group A Streptococcus, the bacteria that causes strep throat and invasive skin infections, while leaving human cells untouched. The other end of the homing beacon is alpha-Gal, a type of sugar molecule. Humans naturally produce antibodies against alpha-Gal, since alpha-Gal is foreign to humans, though other mammals and some microbes produce it. Humans have evolved antibodies against it from eating meat or being exposed to alpha-Gal-generating microbes in the environment.

The idea to use a homing beacon to fight pathogens came from Nobel laureate and study co-author Kary Mullis, who is known as a key pioneer in the area of polymerase chain reaction. Mullis is chief scientific advisor to Altermune Technologies, which funded the study. Nizet tells DDNews that Mullis developed the concept after considering the role of alpha-Gal in the human body. Most other animals and some bacteria express the sugar, says Nizet, and through eating meat and exposure to these microbes, humans develop a striking abundance of anti-Gal antibodies, a fact that was first discovered when attempts to transplant a pig heart into a human resulted in immediate rejection, apparently because the anti-Gal antibodies attacked the epitope present on the pig cells.

“Kary Mullis had the idea that instead of having these antibodies get rid of something we want in our body (the transplanted organ), can’t we harness them to get rid of something we don’t want in our bodies, like a drug-resistant bacterial pathogen,” says Nizet. “He had been working with aptamers, which can be evolved to bind targets with high affinity through the SELEX procedure, and saw them as a perfect platform to modify with alpha-Gal to direct these preexisting antibodies to their target.”

Researchers tested the homing beacon against live strep bacteria and found that Alphamers can bind strep and recruit anti-Gal antibodies to the bacterial surface and also help human immune cells engulf and kill the Alphamer-coated bacteria. The researchers screened for Alphamers that strongly bound to strep and identifyied the molecular target of the Alphamer on the bacteria. They then showed that Alphamers could redirect pre-existing antibodies from human blood/serum to the surface of the strep bacteria in an alphamer sequence-specific and alpha-Gal-specific fashion. These antibodies promoted neutrophil and whole-blood killing of the bacteria.

According to Nizet, the homing beacon concept should theoretically work just as well for bacterial strains that are highly resistant to multidrug treatments. “A doctor could have a suitcase full of pathogen-specific aptamers to create instant immunity to the pathogen once it is diagnosed,” he says. “This conceivably should work for even highly multidrug-resistant strains, as the principle is entirely different than antibiotics. Also, the aptamers would have no effect on the normal human microbiome—all those ‘good citizen’ bacteria that are so important to our health and immunity.”

The study offers the first proof of concept that Alphamers have the potential to specifically redirect preexisting antibodies to bacteria and rapidly activate an antibacterial immune response.

“Our next step is to test Alphamers in animal models of infection with multidrug-resistant bacteria that pose a public health threat, such as MRSA,” said first author Sascha Kristian, visiting research scholar at UC San Diego and associate research director at Altermune Technologies. “Meanwhile, we’ll also be tweaking the Alphamer to make it more potent and more resistant to degradation by the body.”

Nizet says that if Alphamers continue to show promise, researchers might be able to apply the same concept to attack any type of bacteria or virus, or perhaps even cancer cells.