Chemical Harpoons: bacterial anchors

24 June 2015

Interview with

Professor Ulrich Schwarz-Linek, University of St Andrews

To invade or even just to colonize our bodies, microorganisms need to be able to adhere to surfaces to stop themselves being, quite literally, washed away. Previously, microbiologists had identified the bacterial equivalentAn internal thioester in a pathogen surface protein mediates covalent host binding of Velcro, sticky materials which could interact reversibly with cell surfaces to help microbes to cling on. But now, Uli Schwarz-Linek at Saint Andrew's has discovered an entirely new form of adhesion system. This one's the microbial equivalent of super glue. It's a chemical entity that forms a permanent covalent bond to a host's surface, locking the bug in place. He explains to Chris Smith...

Uli - What we're interested in are ways in which microorganisms set up home in our bodies and attach to our tissues, and we are interested in discovering the exact mechanisms by which they achieve that, because if they can't adhere to our tissues, they're simply flushed away by swallowing or a coughing.

Chris - And if we can understand how these things work, that may give us an inroad into designing novel therapeutics, wouldn't it? Because we would be able to potentially dislodge and detach these organisms from the surfaces they're trying to cling on to.

Uli - Absolutely! That is the point. Yes.

Chris - What's new here then? Because we've known for a long time that these microorganisms must have an ability to cling on to surfaces, and we know that they produce little extensions from their surfaces that are almost like miniature molecular grappling hooks that can cling on to things.

Uli - The main difference is that all that has been known previously about how microorganisms bind to human tissue. If you take a very close look at it at great magnification, if you'd like, it looks a little bit like Velcro as you say, their little hooks out to fit together with loops, if you like, on the host's surface. What we hypothesize most that the bacteria have developed a molecular tool, a molecular weapon that, if you compare it to Velcro, it's a little bit like super glue. You do not need large areas of contact to provide strong binding. But instead, you have an extremely strong interaction that doesn't require a large surface.

Chris - Is that not potentially deleterious for the bug though? Because as anyone who has used super glue knows - yes, it's great for gluing the heel back on your shoe when you need it in a hurry but get it on two fingers next door to each other and you've got a problem. It's a trip to casualty. Does there not come with this a danger that the microbes could end up sequestered permanently where they don't want to be?

Uli - To be honest, we do not know. However, what know is that many of bacteria that we are working on have also already come up with a solution to that problem because they have tools to cut off the link again.

Chris - What is the molecule, and how do they do this?

Uli - The specific class of molecules we were working on is a protein that is anchored on the surface of the bacteria, and these are rod-like molecules. And the very tip contains what we refer to now as a chemical harpoon. It will recognize the host's surface and then form a chemical bond. It will undergo a chemical reaction and the chemical reaction means there is a very strong connection formed that cannot be broken easily anymore.

Chris - This is what chemists refer to as a covalent linkage or covalent bond, isn't it? What's performing the covalent linkage? What chemicals are involved?

Uli - Yes, this is a covalent bond, and all you need is a particular bond within the protein and that is really the starting point, the discovery of this unusual bond which we call a thioester. This thioester will react specifically with certain groups on other molecules and these groups are, as we discovered, a side chain of one particular amino acid and that amino acid is called lysine.

Chris - Do all bacteria, do you think, have this or is it just a sub-set?

Uli - As far as we can tell for now, it is a sub-set of bacteria but it's a large sub-set. We found these proteins exclusively in the class that we would call the gram-positive bacteria.

Chris - How do the bacteria keep their powder dry, so to speak? When they're making this intensely sticky chemical, how do they stop it accidentally going off in their face? So, in other words, it's not armed and dangerous until it's deployed onto the surface of the microbe in the right context at the end of that rod?

Uli - We are not entirely sure how that occurs yet, but our hypothesis now is that for the reaction to occur what you need to have is a very specific binding partner. If you mix our bacterial proteins with any other protein, there's no reaction whatsoever. And it's only when the very specific binding partner is found that the reaction occurs. How exactly that happens, we do not understand yet.

Chris - Is it inducible? Can the microbes upregulate and downregulate it? So that they can effectively express it when they want it?

Uli - The answer to that I think is yes, at least for some of the proteins that are better understood. The protein we very much focused on belongs to bacteria called Streptococcus pyogenes. And we know that this chemical harpoon protein we were studying is made by the bacteria particularly when they are exposed to oxygen when the bacteria are about to enter the body. And these bacteria target our tonsils in the throat in particular.

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