As different strains of staph evolve and become increasingly resistant to common antibiotics, such as penicillin, researchers are looking for new ways to treat these infections. Juliane Bubeck Wardenburg, MD, PhD, assistant professor in the Departments of Pediatrics and Microbiology, published a recent study in the Journal of Infectious Disease about a cell receptor called A-Disintegrin and Metalloprotease 10, or ADAM10, that could give doctors a new way to fight these infections. I spoke to her about how staph does its damage, and how turning off this receptor could lead to more effective treatments.
Are there good ways to treat staph infections now, or are we losing ground?
I would say losing ground is the best way to think about it. There are certainly strains of staph in the community as well as in the hospital that are resistant to the antibiotics that used to be the front-running, very potent antibiotics. These are the so-called methicillin-resistant, or MRSA, strains. Now drugs like penicillin, which used to be a real workhorse, aren’t useful for many of these strains. The nature of the disease that the damage both drug-sensitive and drug-resistant staph can cause is quite significant, so sometimes even if you have a good antibiotic, the patient can be so ill that you’re challenged to treat it successfully.
How does a staph infection attack the body?
Staph is one of the most interesting bacteria that cause infections in humans, because essentially any tissue in the body can be affected. For instance, if a bacterium can cause infection in the lungs, it may only need a certain set of strategies that help cause infection. Staph aureus can cause infection anywhere in the entire body, so it has a really elaborate toolbox. It can fight off immune cells in the bloodstream; it can injure the blood vessel wall; it can creep through the blood vessel wall and get out into the tissue and injure the tissue once it arrives in this location. If you have staph in the blood, it can end up in the lung, or the brain or in the joints – the bug has a phenomenal armamentarium of tools that all work together in some manner to attack the human tissue.
Is that toolset something unique to staph aureus?
There are certainly other bugs that can cause a spectrum of disease in different tissues, but staph is the one with the broadest range of capabilities. And that makes it hard to treat as well, because treating an infection in a joint is different than treating an infection in the lung. Treating an infection in the middle of a bone is really different than on the skin. The clinical problem posed by staph is unique and challenging.
In your new study you found out that a cell receptor called ADAM10 helped staph do its damage in cells. How does this work?
The bacteria make a toxin, which is essentially a weapon that’s shot out of the bacteria, almost like a bullet. When it hits the host cell, it pokes a hole in the cell. ADAM10 is the dock for the toxin on the host cell. The toxin has to have a way to stick to the host cell and find the right place to be active, so ADAM10 is that molecular beacon where the toxin binds.
Did you already have an idea that ADAM10 was involved in this process?
The toxin itself has been studied for close to 100 years. It had been unclear whether there was a receptor and what it was, so we just identified that about two years ago. In the intervening time we’ve started to really understand how ADAM10 works as a toxin receptor. The interesting part of the story is it’s not just a docking site. It’s not just that the toxin sees it and sticks to the receptor; it actually uses the receptor for its injurious purposes.
So how can knowing this lead to a better way of fighting staph infections?
I think the big paradigm shift with this research is that we can now actually target the host by disabling the functions of ADAM10. Sometimes it’s hard to target the bug itself with vaccines. There is currently no vaccine available for staph – the development of such a vaccine has been the most elusive goal in the field. What we see for the first time in our study is that if you disable ADAM10 you can disable the toxin, because the toxin absolutely requires the action of ADAM10 for its evil purposes. So you could target ADAM10, which is fairly constant among humans. Your ADAM 10 is probably identical to mine and to everyone else’s in my laboratory. It becomes a different way to think about changing the disease spectrum.
What could you do then to short circuit ADAM10 in the cells?
ADAM10 works like a pair of molecular scissors. When it’s active it can cut other proteins. There are inhibitors that prevent ADAM10 from acting like this pair of scissors, essentially like tying a rubber band around the end of them so they’re not going to open and cut anything. That’s a strategy that we’ve demonstrated as useful in three different types of staphylococcal disease, and it’s amenable to small molecule drug development.
Another strategy is that you could conceivably make an antibody that would block the ability of the toxin to stick to ADAM10. You would eliminate the activity of the toxin because it doesn’t have a dock anymore. So there are a couple of different modalities, both of which are achievable with current molecular approaches to therapeutics.
Is there a downside to blocking ADAM10? Does knocking it out cause problems?
I feel pretty comfortable in the concept of targeting ADAM10 for infection, because the therapy is time-limited. It’s short term. Your window of opportunity to intervene for a severe infection is one to three days. Since the cells in the body regenerate their proteins, even if you knocked ADAM10 out for two or three days in every tissue, I suspect that the individual would be fine. This strategy would allow the person to get a leg up on the infection, and then once they survive they’ll start to make more ADAM10 again. So whatever ADAM10 you’ve disabled will be gone and new protein will be available for use. This margin of safety is borne out both in our animal studies and in prior human clinical trials targeting ADAM10 for other reasons.