Antibody Pries Loose Bacteria’s Grip
News May 18, 2015
When a bacterium “shakes hands” with one of our cells, it might not let go. The handshake, in this case, is between an attachment protein, which is a sort of three-fingered hand at the end of a fimbrius, one of a bacterium’s many “arms,” and one of the innumerable sugar-like molecules that stud the surfaces of human cells. The attachment protein can be tricked into grasping other things, leaving our cells unmolested, but even so, bacteria often manage to get a hold of our cells anyway, by one sleight of hand or another.
Fortunately, the bacterial hand is not always quicker than the scientific eye, as a team of scientists at the University of Washington has demonstrated. These scientists, led by Evgeni V. Sokurenko, Ph.D., took a close look at strains of Escherichia coli that cause urinary tract infections. What the scientists saw helped them figure out how an attachment-protein-blocking antibody failed to prevent urinary tract infections in humans. By learning what the bacterium had up its sleeve, the scientists were able to come up with a better antibody—one that made good use of an unusual hold of its own.
A common bacterium-blocking strategy is to fill the attachment protein hand with an antibody. The attachment protein, however, isn’t static. It fluctuates between strong- and weak-gripping conformations, so it can slip loose and resume its greeting-line ways. Worse, the bacterium can seize free-floating sugars, which effectively compete with antibodies, making them less effective.
The researchers, however, hit upon another approach. They deployed an antibody that works “parasterically”—from the side. Essentially, the antibody takes hold of one of the attachment protein’s fingers, keeping the attachment protein in a more relaxed conformation. The antibody can even seize the finger if the attachment protein is already in a closed conformation, loosening the attachment protein’s grip. Thus, the antibody may serve not only as a vaccine to prevent bacterial infection, it could be used to treat an infection that has already started.
This finding appeared, in an article entitled, “Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli.” This article described how an antibody called Ab926 was able, through parasteric inhibition, to prevent bacteria from attaching to the sugar mannose. In addition, Ab926 could force the bacteria that were already attached to let go, something the other antibodies evaluated in the study could not do.
“Here, using monoclonal antibodies against a vaccine target protein—fimbrial adhesin FimH of uropathogenic E. coli, we demonstrate that unusually strong receptor inhibition can be achieved by antibody that binds within the binding pocket and displaces the ligand in a noncompetitive way,” the authors wrote. “The noncompetitive antibody binds to a loop that interacts with the ligand in the active conformation of the pocket but is shifted away from ligand in the inactive conformation.”
The authors added that the receptor-blocking mechanism of the parasteric antibody is very potent in blocking bacterial adhesion, dissolving surface-adherent biofilms and protecting mice from urinary bladder infection.
"FimH is like a three-fingered hand that closes around the mannose when it binds," Dr. Sokurenko explained. "But the pocket is dynamic and intermittently tightens and loosens its grip." This makes sense, he continued, because the bacteria need to be able to release themselves and move if they're to travel around the urinary tract and invade tissues.
In the case of FimH, the loosening takes place when one of the fingers lifts away, momentarily relaxing the pocket's grip on the mannose. What appears to happen is mAb926 binds to this finger when the pocket is in this relaxed state and prevents it from closing again. As a result, FimH is unable to hold onto the mannose and lets go.
This parasteric action has two advantages over the classical antibody action, the University of Washington scientists explained. First, unlike the other type of antibodies, this antibody does not have to compete with free-floating mannose for access to the FimH pocket. This means it should be more effective at disabling FimH before it binds to its target.
Second, because it can also act on FimH even after bacteria has attached to bladder cells and disable its pocket whenever it relaxes its grip. This raises the possibility that antibodies of this type could be used to treat established E. coli infections by loosening the bacterium's grip so it can be flushed off the wall of the bladder and urinary tract.
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