Corrie Detweiler, PhD, Microbiologist at CU Boulder talks about re-sensitizing antibiotic resistant bacteria to antibiotics.
Interview conducted by Ivanhoe Broadcast News in February 2019.
How dangerous are antibiotic-resistant infections to human health?
CORRIE DETWEILER: The problem with antibiotic resistant infections is that we’re increasingly seeing more and more of them. We need antibiotics in order for us to have elective surgeries, like a knee surgery. We need antibiotics in order for women to survive childbirth or patients to survive cancer treatment. We need antibiotics, for instance, to treat everyday infections that children get on the playground. However, they’re not working as effectively or as frequently as they used to; this is the big problem that researchers are trying to solve.
Without antibiotics, could a minor infection turn into a life-threatening infection?
CORRIE DETWEILER: Yes. If you happen to get a playground infection that includes or has a multidrug-resistant bacterium, when we try to treat it, our treatments aren’t effective. The infection can spiral out of control if the patient’s immune system can’t take care of it.
So, it doesn’t have to be a big, scary superbug. It can be something everyone is exposed to every day.
CORRIE DETWEILER: The ones that we can’t treat are what people call superbugs, which makes it sound like it’s one thing, but when you look at it, it’s a gradient. A long time ago, most bacteria were sensitive to antibiotics. They’re increasingly resistant in terms of degree and the number of antibiotics to which they are resistant. A doctor will try to treat a patient with a particular antibiotic, and it won’t work well, or it won’t work at all and then they have to try another one. However, while the time is passing, and the infection is getting worse for the patient, it becomes a complex, nuanced problem that may end with the death of the patient. You can’t assume that antibiotics are going to work, whereas, when you gave an antibiotic 40 years ago, it worked.
Can you tell me a little bit about perfect antibiotics?
CORRIE DETWEILER: When we first started, the first antibiotic made in large amounts was penicillin. It was really helpful in World War 2, and a lot of soldiers made it home because they could take penicillin. Then we started using it stateside for regular patients who had infections. In fact, penicillin saved my mother’s life when she was a little kid. However, back then, when antibiotics were used, we knew they would work, because while doctors had seen resistance, they were generally isolated cases. Now they are not isolated cases; that is the fundamental problem. Many people get resistant infections from being on a regular playground or from walking around their town. Resistant bacteria are everywhere and they do not discriminate.
Do you think we will be able to find a perfect antibiotic, like penicillin, again?
CORRIE DETWEILER: I think the days when you could give a patient an antibiotic and you knew they wouldn’t have a resistant infection are pretty much gone. What we’re moving towards, is not finding perfect antibiotics that quickly clear infections, but towards trying to find compounds that help manage infections, hopefully long enough for the patient’s immune system to do its job and eradicate the infection.
What kind of impact would it have on human health if we continue to see more cases of antibiotic-resistant infections?
CORRIE DETWEILER: Not being able to treat bacterial infections is an enormous problem, because our medical system is dependent on antibiotics. You cannot have an elective surgery without getting a prophylactic antibiotic, or at least having that prescription to go home with in case you get infection. Childbirth often requires treatment with antibiotics to allow women to survive past the actual childbirth and not get a lethal infection. All of medicine will change because modern medicine cannot survive without antibiotics. When you treat a cancer patient, generally the drugs incapacitate the immune system and we need to have antibiotics for those patients to be able to survive the cancer treatment. If antibiotics don’t work, it’s going to change how we treat people and what we can treat them for, whether or not you can have an elective surgery, and whether or not your friend will survive childbirth. Those will be major conceptual and cultural changes.
Are people who are getting these antibiotic-resistant infections dying?
CORRIE DETWEILER: We see people who were healthy get an infection that we can’t treat. They go through multiple rounds of antibiotics and some of them die. This will increasingly happen.
Are flu-related complications directly related to antibiotic-resistance?
CORRIE DETWEILER: Yes. Many patients who die of flu these days, and also in the 1918 flu, didn’t die per se because of the damage that flu caused; they died due to secondary infections damaging their lungs, which prevented them from breathing. In fact, in the 1918 situation, they would often find young, healthy servicemen around 22 years old that would turn blue; they got cyanosis before they died because a bacterial infection prevented them from breathing. The flu wasn’t what killed them; it was a bacterial infection. And if we can’t treat that infection, what are we going to do?
Tell me about what you guys are studying here. What are you looking for?
CORRIE DETWEILER: We’re trying to discover, and then develop, new chemicals or natural products that could be used to treat bacterial infections.
If you’re not looking for a new penicillin, are you trying to get the old antibiotics to work better?
CORRIE DETWEILER: Yes. What we’ve done recently is we’ve been able to find some chemical compounds that prevent bacteria from pumping out antibiotics. One way bacteria can become resistant to antibiotics is by acquiring efflux pumps, which pump out antibiotics. If we can inhibit those efflux pumps, then we re-sensitize that bacterium to a particular antibiotic. That’s its utility. It’s not a silver bullet and it’s not perfect, but can we make a bacterium, and therefore an infection, more sensitive to an antibiotic that we already have.
What have the early results shown? What have you found?
CORRIE DETWEILER: So far, we have compounds that we’ve been able to improve in collaboration with medicinal chemists at this company called Crestone, which is in Boulder, Colorado. You find a certain compound that has a certain structure and you make analogues of it. You could remove the thumb, or you add a second thumb, for instance. You make different chemicals, and then you test them to see if they have better activity; they’re more potent and less toxic to the mammal, the human. We’ve taken a step forward in that, and we now have compounds that work at sub-micromolar concentrations and that are fairly nontoxic for eukaryotic host cells, for mammals.
How many compounds have you looked at? How many worked?
CORRIE DETWEILER: We screened through about 14,000 compounds, and we found three that look like they inhibit efflux pumps. We have since worked to change those compounds with the company Crestone, their medicinal chemists, to make different kinds of chemicals that they think would work better. Some of them work better, and some of them work worse. The ones that work better are the ones we are now studying.
How did you test its efficacy against Salmonella?
CORRIE DETWEILER: We test efficacy in cell culture. We have mammalian cells that we infect with bacteria, and then we ask, does a compound work in that context? That’s a good system because if the compound is toxic to the cells, we’re going to see dead mammalian cells. If the compound is not toxic to the cell but kills the bacteria, we can see that too. That’s our central system. Other laboratories have worked on this kind of system, and we’ve been pushing as hard as we can to look for efflux pump inhibitors.
The compounds synergize with the common antibiotics erythromycin and ciprofloxacin to reduce replication of Salmonella in infected cells from 10 to 24. That’s the study we’re talking about now.
CORRIE DETWEILER: Yeah.
Explain what that means, synergize with erythromycin and Cipro.
CORRIE DETWEILER: Erythromycin and ciprofloxacin are both antibiotics that are exported by efflux pumps. They’re exported by the particular kind of pump that our compounds inhibit. When we say there’s synergy, what we mean is that if you treat with antibiotic and you treat with efflux pump inhibitor, you get better killing of the bacteria than you would predict by just treating with either alone. That’s what that synergy is. What we predict is that you would treat patients with efflux pump inhibitors and classical existing safe antibiotics at the same time; this way you’re only adding one new thing to the equation to make the bacterium more sensitive to an existing antibiotic.
Ideally, how would the efflux pump inhibitor be given? Is this a pill that someone would take right along with the antibiotic?
CORRIE DETWEILER: Ideally, any drug is given orally because it is convenient, and you can easily take it multiple times a day. In reality, I would be happy if we could develop an I.V., an intravenous, methodology. It’d be better to have an oral drug, but if we could develop efflux pump inhibitors as something that would work in the hospital intravenously, that would be terrific. That would be a major step forward.
Are there people working on efflux pump inhibitors? Or is this a new area of research?
CORRIE DETWEILER: I think people started working on them in the late ’90s. However, they hit this wall of toxicity; the inhibitors people found were toxic to whole animals. What we’re hoping to do to get around that is medicinal chemistry. We test new analogs in the cell culture systems; if a compound is toxic, we might be able to identify it early and not continue to work on it, rather than find out it is toxic later. Our goal, and other labs are trying this too, is to develop non-toxic efflux pump inhibitors.
Where did you say the most promising compound that you have now came from?
CORRIE DETWEILER: It’s from chemical synthesis, which is our collaboration with Crestone. They’ve made analogues of our compound, and that’s what we’re working from.
Let’s fast-forward 10 years or so and say this goes just as you hope it will. What does that mean? How could this change our health?
CORRIE DETWEILER: What we’re hoping is that our lab, and also other labs across the country, develop new ways to treat infections. Being able to re-sensitize bacteria to infections is just one way. For example, women in the US now are getting UTIs – urinary tract infections – that we cannot treat. Maybe we could treat them again with a standard antibiotic and an efflux pump inhibitor to clear their infection. It’s enabling people to clear infection rather than suffer from chronic infections, or possibly not survive, that matters. The antibiotic-resistance problem is major, and it’s a situation where people we now assume will survive no longer will. It will radically change how we think. If you thought that your nephew who fell off a skateboard and damaged his elbow with a massive cut, if you thought that he’d be dead in three weeks; you would think very differently about this situation than you do now.
Could this happen to healthy people?
CORRIE DETWEILER: Yes. For example, the UTI infections often occur to women in their 20s to 40s; they’re young and healthy.
How can an infection like that kill someone?
CORRIE DETWEILER: If you have an untreatable infection, the bacteria can keep replicating. Your immune system cannot contain the microbe and that can lead to sepsis, or a bacterial infection of the blood. Sepsis often leads to organ failure and death.
Does it take over your whole body regardless of where it starts? Does it keep replicating?
CORRIE DETWEILER: Yes. It could spread from your elbow, which is not an essential organ, to essential organs. For example, if it spreads from the elbow to the blood and then to all organs, it will likely be fatal.
What’s the next part of your research?
CORRIE DETWEILER: We need to do more medicinal chemistry on these compounds. We need to further improve them, and we need to start taking them into animal models. Then, we’ll take them into the clinic. It’s a slow process and there’s no glamour in it; There’s no glory. However, if you can make a difference by developing a compound that would reduce death from bacterial infections, that would be terrific.
Timeline-wise, or best-case scenario, is it 10 years out?
CORRIE DETWEILER: Best-case scenario – which would require some changes and regulation – is five to 10 years out. There’s hope that we get through sooner with these kinds of compounds because they’d be working in tandem with a known antibiotic that has known properties. However, it’s not really clear. It is really difficult to get antibiotics through the regulatory situation right now; this is one of the reasons why companies are dumping antibiotics. They’re just stopping to work on them.
Is it because antibiotics are not big money-making drugs?
CORRIE DETWEILER: Yes, exactly.
Are they not getting enough funding?
CORRIE DETWEILER: Yes. This is the place for academia. Big bucks are not going to be made off of antibiotics unless we radically change our system. People don’t want to pay more than $500 for an antibiotic, and they will only take it for eight to 10 days. That’s all they hopefully need to take it for. It’s not a cancer drug where you can take it for years, and we could charge you $100,000 a year. The economics behind antibiotics is really difficult, and that’s why Big Pharma has been leaving the field. If you look at who’s left developing antibiotics, it’s small companies, and many are struggling.
What would it take to get their money back into it?
CORRIE DETWEILER: Legislative change. There are bills that are being discussed in the House of Representatives right now, but we’ll see how far they get to go.
Is there anything that the general population can do to protect themselves? Or is it just kind of lucky and unlucky?
CORRIE DETWEILER: Lucky and unlucky is a big factor. However, when you have a small infection, like in your thumb, treat it; put Neosporin, alcohol, or Bactine on it and don’t let it get to the point where it’s red and painful, which means it’s growing more serious and might spread. It might not help, but at least it’s something you can do to reduce the chance of developing a life-threatening infection.
What do you suggest for a mild or minor cut?
CORRIE DETWEILER: If it starts to hurt or spread, you need to treat it right away, even if it’s small. If it starts to really hurt, this infection is getting more serious.
When someone does have an infection and they don’t want to take antibiotics, will it cause an antibiotic-resistance?
CORRIE DETWEILER: No.
What should you do if you’re prescribed an antibiotic?
CORRIE DETWEILER: You should take it and follow the instructions; take it when instructed and take the entire course. That’s how you can best protect yourself.
What is the deeper science that we might be able to explain and should explain?
CORRIE DETWEILER: Selling the antibiotic is a really hard science problem, and a hard-political problem too. Companies must be able to earn money off antibiotics or the government needs to put funding into developing new antibiotics. Those are the only two pathways that we’re going to get new antibiotics from.
Are we just hoping that one of those works at this point?
CORRIE DETWEILER: Yes. Or both. It’s going to become a known issue when enough people – like your nephew’s scrape from a skateboard accident, or your friend who just had a baby – that you think shouldn’t die, who currently would not die, actually start dying of infections. That’s when we’ll start paying attention.
Do you think that 80,000 people dying of flu-related complications last year wasn’t enough to kick it? Or you think it needs to be a lot more than that?
CORRIE DETWEILER: I think it needs to be more than that. Many of the flu patients ended up getting infections. However, a lot of the people who get untreatable infections are older, and therefore we dismiss them just because they’re older, and we think ‘how long should you live anyway?’ There’s a lot of attitude in there. It’s going to change when we see younger people dying.
For the people who died of the flu-related complications, at least some of it was because of bacterial-resistant or antibiotic-resistant pneumonia?
CORRIE DETWEILER: Some of the people who have flu find that their lungs become vulnerable to bacterial infections. If those infections are resistant to antibiotics, then they’re difficult to treat. And of course, a lung is an essential organ.
Are we seeing that more and more?
CORRIE DETWEILER: Yes, we are seeing that resistant-infections continue to grow and spread.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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Corrie Detweiler, PhD
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