Michael D. L. Johnson, PhD, Asst Professor of Immunobiology at the University of Arizona talks about using copper as an antimicrobial.
Interview conducted by Ivanhoe Broadcast News in May 2019.
Let’s talk a little bit about copper. We were saying a minute ago, it seems like basic science. Bacteria doesn’t like copper, but I’m sure it’s a little bit more complicated than that.
JOHNSON: It actually is a little bit more complicated than that. And those complications are still some of the things that we’re trying to figure out in this lab. There have been previous things that said oh copper kills like this, copper kills like that, and we’ve tried to try and drill down into what these mechanisms are. So our lab really wants to do two things here, and it’s kind of what scientists do in general. We want to understand how something works and then we will either break it or make it better. In the confines of copper, which we can use to kill bacteria and bacteria that are not good for us, that is, we want to actually understand how the copper works and then break or kill the bacteria. And to do that, we need to actually understand how the copper works and what the bacteria are trying to do to get rid of the copper. And in the process, we can actually target different pathways that the bacteria uses to try and come up with new therapeutics to hopefully overcome some of these anti-microbial or antibiotic resistance stress.
Antibiotic production has really declined as of late.
JOHNSON: That is true. And the wonderful thing about copper is that, even though bacteria have been susceptible to copper toxicity since antiquity – since they used to make copper pots to store their soups in The Times of Persian kings, it’s still toxic today, which is a fantastic thing. Even our bodies take advantage of that. We have cells in our body called macrophages. They’re like these garbage collector cells. They engulf the bacteria, put them in this little compartment of death and in doing so they actually do a number of things. They lower the pH making an acidic environment – not good. They have these oxidizing bursts – that’s also not good. But they also do something called nutritional immunity, where they take some of these necessary metals that the bacteria need, things like iron, things that you’ll see at the bottom of your vitamins, that are metals. But it also bombards it with things like copper. So our body takes advantage of that still to this day. So there’s something to it, and we’re trying to figure that out.
How have you been testing this over the past few years?
JOHNSON: We have been going from atom to animal model doing everything in between. So we do lots of different techniques in this particular laboratory to try and address the problem. So one of the things we do is structural biology, which is basically getting a snapshot of what a protein looks like on a molecular level. We do molecular biology in which we try and manipulate the genes inside of the bacteria. So that’s like a molecular microbiology kind of thing. We do biophysics or biochemistry trying to understand the rates of on and off on how proteins interact with each other or DNA. And we also do animal models of infection. And this is how we actually find therapeutic targets. We take a bacteria. We say I think this gene is important for infection. And if it’s important for infection, it’s something that we can develop a therapeutic toward it. But how do we know that it’s important? So we actually have models of infection. We can add it to cell cultures, see if it binds, see if it adheres, see if it makes toxins, see if it makes an animal model sick so that we can say oh you know what? If we cripple this particular gene, all the sudden the bacteria can’t cause disease anymore. We have a potential therapeutic target. And there are a lot of these proteins out there that we can actually use and try to kind of find little small molecule inhibitors here and there. And for us, we’re trying to concentrate on things that actually synergize with copper to work with those particular things.
Like what?
JOHNSON: Well, I’m bound to secrecy by tech transfer. So we actually have a compound right now that’s doing pretty well in our in vitro studies that we’re able to kill a lot of bacteria really quickly. We can go from maybe 107 bacteria, which is a lot of bacteria and we can basically kill ninety nine point nine percent of that population in about two hours using things that work with copper to kill the bacteria. So we’re very excited about this new direction in the lab, and I think it has the potential to help a lot of people.
It’s not copper itself. It’s something that you’re adding to copper.
JOHNSON: It’s something that we’re adding – it’s a copper synergizing compound.
So you still need the copper?
JOHNSON: You still need the copper. So we can add A – no effect. We can B – no effect. But A plus B – bam, got them.
From what I read in the news releases, it’s pneumonia that you’re turning first. Is that accurate?
JOHNSON: So, it is pneumonia and that’s the prevalent disease caused by the bacteria that we look at. So we look at Streptococcus pneumoniae, which is a causative agent of a lot of things – pneumonia, it can go into the bloodstream for sepsis. It’s also really big with ear infections, so a lot of the ear infections that kids get is actually bacterial through Streptococcus pneumoniae. So luckily there is a vaccine for it, which is very effective. I just came from some very nice surveillance talks at the conference I was at. You could see all the infection rate just plummet with the strains of Streptococcus pneumoniae due to the vaccine. Unfortunately, there are strains that are not covered in the vaccine that are starting to rise, and further they are actually antibiotic resistant. So, what do we do about those? So with a bacteria that still kills 1.5 million people per year with 50 percent of those being under the age of five, we’re trying to find new treatments and we’re doing that through copper.
Where are you in your research right now. Early? Close to trials?
JOHNSON: I think we’re pretty far away from trials right now. What I’m learning in being here, there’s a lot that needs to be done before you get to that point because the goal is to not only help the person get rid of the bacterial infection, but to also do no harm to them. So we want to make sure that the products that we’re coming up with are completely and totally safe for the person to take, but toxic against the bacteria. So right now, we’re really trying to figure out well what is the mechanism? How does it work? You know, get down to the atom level of how does it bind? You know, we want to know anything and everything we can know about these particular compounds to really have a much better effect.
How would the patient get the copper? As you said, it’s not like wearing a copper bracelet.
JOHNSON: If you wear a copper bracelet, right around that copper bracelet is gonna be very sterile, but nowhere else. You know, it’s not going to rub off on your whole body. It wouldn’t work like that. You actually get copper from a variety of root vegetables and anything that comes from the ground, there’s actually a higher amount of copper. I know two milligrams does not sound like a lot, but that’s actually the daily recommended value for humans to actually take. And the thing is you can actually have hypo and hyper copper diseases in humans. Like, you have too much and too little. But by and large humans are very good at regulating copper. But bacteria are not.
Would you be taking a pill? Would they just have to eat more vegetables?
JOHNSON: How would they get the copper? They would hopefully just continue on with their normal diet. Your body has a very good way of kind of taking the copper from point A to point B where it needs to be in your body to accomplish the task that it needs. So there are proteins and enzymes that your body needs copper for, but you also again have that little compartment of death that it can sequester the copper and pump it into that particular environment to kill bacteria.
So to use it eventually, you wouldn’t even need to have a pill or IV drip, it would just be a matter of diet?
JOHNSON: Well, with copper, yes. But with the compound if you’re trying to get rid of some of these bacterial infections, then you’d need another mechanism of entry, maybe inhalant, maybe a cream. These are things that we’re nowhere near in trying to get there. We’re just really trying to concentrate on does it work or not, and how does it work?
Will things start to escalate now as far as getting to trials or other studies?
JOHNSON: One of the things about escalating science is you need a good team. And I am so fortunate, so very fortunate, that the people in my laboratory are absolutely wonderful. They make me look very good and I’m very fortunate for that. I think we’re getting to a critical mass of people getting things done and people working together and really a lot of great progress is starting to take place in the laboratory.
You said something about copy with a big Y. How does that fit in?
JOHNSON: CopY is a very interesting protein. Let me go a little bit into kind of how metal import and export work before I talk about the copY. So let’s say you really want iron, which we all do, and also bacteria. They have a lot of import systems for iron and some bacteria don’t even have export systems because they’d rather hold onto it. Then you have things like manganese or calcium. You have import system and export system because you need to be able to acquire it when it’s too little and get rid of it when there’s too much. With copper, by and large there’s only copper export systems. They don’t want it to get in at all. But when it’s in there, they want to get rid of it as fast as they possibly can. So that copY protein is basically the guardian of that particular cop operon or set of genes, they consist of a repressor, so once it sees copper it opens it up and says hey we need to make these proteins so we can get the copper out and then it makes more of the repressor. Then it makes this chaperone protein, which is exactly how it sounds – it chaperones the copper to around the bacteria and eventually it chaperones to this protein called the exporter. So that repressor copY controls that entire system. We’re trying to understand how it controls – what DNA does it bind to? What metals does it bind to to open up or to close? How does it even look? So we’re trying to do structural biology to get that atomic view of that particular protein. It binds one metal and it clamps down and binds another metal and it falls off. And we have no idea how any of this is really taking place at an atomic level. In theory, we can kind of hypothesize and hand wave it a little bit. But we really want to know how that process works because if we can actually find out, maybe we can keep it clamped down on the DNA. And now we have another treatment. We can prevent the bacteria from trying to kick out the copper and bam, now they’re intoxicated with copper and they are less virulent. And we’ve proven that part. But we’re still trying to understand how the system works.
It’s pretty cool that today in 2019 you’re investigating something that people have known forever and it could be the answer.
JOHNSON: In the copper state, no doubt. But it is quite amazing that, you know, I think we thought we knew how it worked. And one person said it works like this and everybody says OK, you’re right. And then we start taking a closer look and says well, if it’s that, we must have to test this hypothesis. And the job of a scientist is not to prove our hypothesis. It’s to actually disprove our hypothesis. We do anything and everything to try and disprove what we think is right so that we can actually prove what is going on. So we say, well, let’s put that under a little bit more stringency to see if that’s true under this condition or this condition or this condition. That’s why a lot of scientists kind of hedge their bets when they’re actually talking about different things. Well, under condition A, given B, equals – you know, instead of saying we cured cancer. It’s like, no, no. Under this condition, we try and be very specific in the language that we use. But in this particular case, we had to take a closer look at how copper actually affected things. Heck, we can spray crops with a copper solution. It’s called the Bordeaux mixture. It actually protects vineyards. You know, copper has been used to actually protect against the potato blight to save potatoes and other crops. We should know how copper works. We should absolutely know how copper works. If it’s doing all these fantastic, wonderful things, we should know how it’s toxic. And we should know how the bacteria tries to fight back against it because if we understand that, the possibilities of therapeutic targets I believe are limitless – well, limited to the number of proteins in the bacteria of course. I always have to add that caveat.
What haven’t I asked you that you think should go in the story.
JOHNSON: I think it’s really wonderful to be in a supportive environment here at the University of Arizona. I’ve been here for three years and I think it’s been an absolutely great experience to work at a place like this. I enjoy my colleagues. I enjoy doing science. I mean they make me not dread coming to work you know which is sometimes hard. But it’s a very nice, collaborative environment here. And I’m just really excited to be working here.
END OF INTERVIEW
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