Antibodies to combat antimicrobial resistance

Antimicrobial resistance is a natural process that occurs when microorganisms that cause disease become resistant to antibiotic drugs. It’s a growing problem; one which former England chief medical officer Dame Sally Davies has described as posing a bigger threat than terrorism. One microbe in particular is proving extremely troublesome, although you may well not have heard of it. It’s called Acinetobacter baumannii, and it isn’t just resistant to one drug, it’s effectively resistant to every drug we have. To the extent that patients need special isolation precautions in hospital to prevent them passing it to anyone else. The mortality rate is up to 50%. But necessity being the mother of invention, two teams have been working recently on a solution. One, based in Hungary and whom we’ll hear from in a minute, is looking at the century-old approach of using bacteriophages - viruses that attack bacteria. But first, closer to home, Steve Baker at the University of Cambridge has developed a way to mass-produce antibodies that can neutralise and prevent infection with the agent, the danger posed by which, he’s emphatic about…

Steve - It's a problem that we hear a lot about, but it's really difficult to emphasise how important it is. There's a real chance that all the antibiotics that we have come to use and rely on are no longer going to be effective. So therefore we are desperate really for new solutions. The reason that we don't have any, or there's nothing that's forthcoming at the moment is because it's been largely neglected for other things in recent years because pharmaceutical companies are less interested in it. And also we've really gone through the whole kind of spectrum of different drugs we think that can kill bacteria and therefore we really need new kinds of alternative solutions.

Chris - What's been your approach instead?

Steve - So what we've done then is think about how we can do things in a slightly different way and work out whether we can kill microorganisms with a different approach. So rather than using small molecules such as antibiotics, we have worked on an approach to try and develop antibodies. So these are naturally occurring, but we can manufacture them to target specific components of the outer bacteria to try and trigger the immune system to try and do something to kill the bacteria instead

Chris - We've got sort of form in this area, haven't we? Because over Covid for example, when you and I saw each other quite a bit, we were making antibodies that would attack the coronavirus and do I presume something quite similar?

Steve - Right. So this is then the reason we really wanted to try it because this approach, so monoclonal antibodies has been used for a whole host of different things including cancer, but also is becoming more receptive for infectious diseases and particularly against viruses. However, it hasn't really been developed or scaled against bacteria. So we are one of the first kinds of groups to try and do this and see whether we can identify things that we can hit with antibodies on the outside of the bug.

Chris - Which bacteria have you gone after then?

Steve - The bacteria we were interested in is a bacterium called Acinetobacter baumannii and it causes really aggressive respiratory tracts and bloodstream infections and particularly people that are hospitalised. And the reason it is so important, is because certainly in many countries in Asia and also increasingly in Europe and the US it is now untreatable with every antibiotic that's currently available. So if you're infected with one of these and you don't trigger a natural immune response to recover, then there's a good chance you'll die from it. So therefore we saw this as a challenge to see, okay, this is a high bar, but can we use this technology to try and come up with something that's a bit different.

Chris - And just to add to that, we do see cases in countries like our own, when people come back from having been overseas or they bring it back with them, don't they?

Steve - Yeah right, and that's the case for most drug resistant bacteria. So I think there's a bit of this is a problem of other countries, particularly poorer countries, but like coronaviruses, bacteria can travel internationally, they don't need passports, and therefore they can end up in hospital and healthcare systems anywhere in the world. So this is a problem everywhere.

Chris - So how have you got round this, what have you gone for on these Acinetobacter bugs, these problem bacteria and how have you coupled it to what the immune system then does?

Steve - Yeah, so our approach was working with a colleague of mine. They had this chimeric mice that allowed us to immunise the animal. And the animal then generated a large immune response to whatever we gave it. So rather than assuming we knew what to target, we gave the mouse a cocktail of different components of the bacterial cell and let the immune system decide which one was the most important thing we thought we could target.

Chris - Once the immune system starts making a response, how do you then get the bit of the immune system that knows how to make that antibody that you want? How do you get that out of the mouse and then turn it into something useful?

Steve - So this is the clever bit because then there's a whole process to do this. So we could mine the cells, they're called B cells. These are cells that produce antibodies and these mice have a human B cell repertoire, which means they produce human antibodies. So there's a mechanism for us to sort those cells. We collect them and then we go through a process of screening each individual cell that we can harvest to try and work out what they're producing an antibody against. So it's a lot of grunt work to really find the matching combination of which antibody and and how and where it's sticking to the bacteria

Chris - That gives you a cell that has the genetic know-how for making an antibody So you can harness that so you can now make these antibodies at scale. How are they used?

Steve - So what we did in this experiment, we used it prophylactically. So we used it like a vaccine. The test that we developed was one where we gave these to mice and then let them develop a short-term response within 24 hours later. And then we challenged them with the bacteria. And the idea would be if we were going to use it in people, we'd either inject it prophylactically or we'd give it intranasally. And then hopefully those people that were vulnerable going into such places where these organisms circulated would then have some degree of instant immunity. The idea long-term probably would develop them into more into therapeutics when if people had these infections then we could then target the bacteria in the same way and and actually specifically choose the immune system to kill those bacteria.

Chris - And have you sussed out how these antibodies are achieving the therapeutic effect on the bacteria when they're there?

Steve - Yeah, so we think that the antibodies stick to the outside of the bacteria and they label it and then they activate certain cell types and that means they get eaten by these macrophages and then they get destroyed. And we think that's a mechanism that these antibodies are performing by and we think that's why we can demonstrate they protect the mice we infect with the bacteria.