How Can We Discover Better Antibiotics?
The problem is antibiotic resistance: Infectious diseases are outpacing the ability of current drugs to fight them. Part of the challenge is in finding new antibiotic sources. Most current antibiotics come from bacteria found in the soil, but Kim Lewis, who directs Northeastern University’s Antimicrobial Discovery Center, says only about 1 percent of soil microbes can be cultured easily in petri dishes.
“But then you hit upon the remaining 99 percent, also known in microbiology as the microbial dark matter, that does not readily grow in the lab,” he says. “And that is a big problem.”
As of last fall, 40 new antibiotics were in clinical development for US markets, according to data from the Pew Charitable Trusts. But Lewis says these new drugs are mainly analogs of existing antibiotics — and while useful, the reprieve they provide will only be temporary. “Resistance develops much faster, of course, to analogs of existing compounds,” he explains. “If you look at completely new classes, there’s almost nothing in the clinic right now. So, the pipeline is really pretty dry.”
But Lewis is part of a group of scientists that’s trying to change that — mining new methods and other crevices for better infection-fighting agents. So is Jon Thorson, who directs the University of Kentucky’s Center for Pharmaceutical Research. His team has even hunted microbes in Kentucky coal mines.
“There’s a long tradition for microbes being a source for antibiotics,” Thorson says. “Drugs like tetracycline, macrolides like erythromycin, aminoglycoside antibiotics are all produced by bacteria. But one of the challenges in our field, really, is, how do you reduce the percentage of rediscovery?”
“So, the way to do that is to go into areas where people haven’t explored. And that’s what brought us into coal mines and other environments that really have not been explored in this regard.”
In the mine, Thorson and his team discovered an enzyme that could make an existing antibiotic more potent. “So, the source of these antibiotics, or these small molecules, are again bacteria,” Thorson explains.
“And they produce not only molecules that have biological activity, but they also have enzymes that are responsible for making them. And sometimes, we can take advantage of those enzymes to do chemistry.”
Meanwhile, Lewis’ research expands the field in another direction: the 99 percent of soil microbes that, so far, have proved too tough to culture in a lab. “My colleague, Slava Epstein, from Northeastern had a very simple idea: We will grow bacteria in their natural environment, where, of course, they do grow,” he explains.
Scientists still aren’t quite sure why certain bacteria are so hard to cultivate in the lab. Lewis says some bacteria depend on growth factors from other bacteria to get iron and other nutrients from the environment. “But that explains about 10 percent of the ‘uncultivability,'” he says. “We still don’t know why 90 percent of the microbial dark matter doesn’t grow.”
Needless to say, Lewis and Epstein developed a workaround. They built a box, called a diffusion chamber, to sequester the bacteria inside its native soil. “Essentially, we take a sample of bacteria from soil, we sandwich it between two semipermeable membranes, and then that diffusion chamber goes back into the soil,” Lewis says.
Nestled cozily inside their home dirt, bacteria in the diffusion chamber don’t know they have been tricked into growing in a lab environment. “And so they start forming colonies,” he says.
The diffusion chamber is already giving up secrets: In 2015, Lewis and his colleagues announced that bacteria from a grassy Maine field yielded an antibiotic they called teixobactin. Still in development, the antibiotic is active against deadly infections like MRSA and tuberculosis.
But Lewis says that in the ever-changing battle against bacteria, we need to stay nimble — and we still have a lot left to learn. “Our best antibiotics, like penicillin, for example, they bind several related targets,” Lewis says. “But if you’re developing a new compound, and it binds only one target, then that will be a problem.”
“And the other very big problem is penetration. So, bacteria evolved a terrific penetration barrier, their cell envelope, that restricts penetration of compounds that look like drugs. So, some antibiotics, of course, are molecules that evolved to penetrate. But we still do not have a very good understanding of which molecules will and which will not penetrate.”
Kim Lewis is University Distinguished Professor and director of the Antimicrobial Discovery Center at the Department of Biology at Northeastern University in Boston, Massachusetts.
Joe Larsen is director of the Biomedical Advanced Research Development Authority in the U.S. Department of Health and Human Services, Washington, D.C.
Jon Thorson is director of the Center for Pharmaceutical Research and Innovation and a professor of Pharmaceutical Sciences at the University of Kentucky in Lexington, Kentucky.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. A bit later in the hour, seven newly discovered exoplanets, all in the sweet spot. We’ve been hearing about it all week. We’ll get the details.
But first, in January, a woman in Las Vegas died from a superbug, an infection that antibiotics were powerless to treat. The bacteria were resistant to the 14 different antibiotics available at the hospital. That’s the latest report of a superbug, but not the first time you’ve heard that we’re heading into a post-antibiotic world.
Bacteria are outpacing the roster of drugs that we currently have. The obviously simple question is, why don’t we make more antibiotics? If only the answer was that simple. It involves more questions like, where should we look for these new drugs? And what is the trick to formulating a drug that can get past the defenses of a bacterium? Of course, there’s always the money.
My next guests are here to talk about that. Kim Lewis is the director of the Anti-microbial Discovery Center at Northeastern University in Boston. John Thorson is the director of the Center for Pharmaceutical Research and Innovation at the University of Kentucky in Lexington. Welcome to Science Friday.
JOHN THORSON: Good to be here, Ira.
IRA FLATOW: John, you hunt for antibiotics in places that people wouldn’t even think to visit. You go to coal mine fires, right?
JOHN THORSON: That’s right.
IRA FLATOW: What about the environment made you think there might be valuable antibiotics down there, for example?
JOHN THORSON: Well, microbes, or bacteria– there’s a long tradition for microbes being a source for antibiotics, drugs like tetracycline, macrolides like eurythromycin, the aminoglycocide antibiotics are all produced by bacteria. But one of the challenges in our field really is how do you reduce the percentage of rediscovery? And so the way to do that is to go into areas where people haven’t explored, and that’s what brought us into coal mines and other environments that really have not been explored in this regard.
IRA FLATOW: And what you found in the coal mine wasn’t a new antibiotic, was it? It was kind of an add-on?
JOHN THORSON: That’s right. So the source of these antibiotics are these small molecules– again, bacteria. And they produce not only molecules that have biological activity, but they also have enzymes that are responsible for making them. And sometimes we can take advantage of those enzymes to do chemistry. And that’s really the basis of the study that we recently published.
IRA FLATOW: So it actually improved how the antibiotic worked?
JOHN THORSON: That’s right. That’s right. So it really enabled the chemistry and led to an improvement to an existing antibiotic.
IRA FLATOW: Kim, for how complicated these drugs are, we’re still searching for them in pretty basic places in a pretty basic way. We’ve only isolated– I think this is one of the most interesting statistics I’ve been following over the years– we have only isolated a really tiny amount of bacteria from soil bacteria, right? You and your colleagues developed a device that helps with that problem. First, tell us how difficult it is to get bacteria out of soil.
KIM LEWIS: Right. So it is very easy to get to about 1% of bacteria from soil to grow in our Petri dishes. But then you hit upon the remaining 99%, also known in microbiology as the microbial dark matter that does not readily grow in the lab. And that is a big problem.
IRA FLATOW: And you found a way around that, a unique way. Tell us about that.
KIM LEWIS: So my colleague Slava Epstein from Northeastern and I had a very simple idea. We will grow bacteria in their natural environment where, of course, they do grow. So we came up with a gadget, which is called the diffusion chamber.
Essentially we take a sample of bacteria from soil, we sandwich it between two semi-permeable membranes, and then that diffusion chamber goes back into the soil. So now everything diffuses through this chamber, meaning nutrients, signaling molecules, and bacteria don’t know that we tricked them. And so they start forming colonies. So that is the basic principle of our device.
IRA FLATOW: Do we know why they need to be in their native environment for them to grow?
KIM LEWIS: We know a little bit about it. So one thing that we discover is that at least some uncultured bacteria require growth factors from their neighbors. And so we isolate it, at least one class of such growth factors, and found that they are necessary for bacteria to acquire iron from their environments. But that explains about 10% of the uncultivability. We still don’t know why the 90% of the microbial dark matter doesn’t grow.
IRA FLATOW: That’s fascinating. I know there are 40 antibiotics in clinical development, compared to 700 cancer drugs. Is this really harder than cancer? I mean, why are bacteria so difficult to defeat?
KIM LEWIS: Well, Ira, first of all, these 40 is an overestimate. These are mainly analogs of existing antibiotics. And while that is useful, it only gives us a temporary reprieve, because resistance develops much faster, of course, to analogs of existing compounds. If you look at completely new classes, there’s almost nothing in the clinic right now. So the pipeline is really pretty dry for that.
And to address your question why, well, there is an interesting paradox in our field of anti-microbial discovery is that we did have once a golden era, as we already discussed. We once had an ability to discover new antibiotics from soil microorganisms, and then that was overmined, and that source dried up. And so now the question is where to go and look. And we also look for things that people have not seen before. But we like to look around Boston in our backyards, and then places in New England in general.
So we’re working with a start-up company, NovaBiotics, collecting soils and growing uncultured bacteria from them. And it is then those bacteria that come from very common environments but have been uncultured, so have not been seen before, that are producing interesting new chemical compounds.
IRA FLATOW: John, when you take an antibiotic, are you just releasing out millions of molecules, hoping that one will encounter a bacterium? I mean, do they have surface proteins to help the antibiotic recognize it?
JOHN THORSON: We’re doing a number of focused screens, looking for targeted activities. We’re also doing general antimicrobial activity measures as well. We’re looking at these new bioactive molecules to try to understand their function.
IRA FLATOW: But so it’s sort of like– I’m trying to understand the fascinating mechanism of how drugs work. You take a drug. You take an antibiotic. You release it into the blood. It’s just like, do you flood the blood, hoping that it links up with the bacterium, and it’s sort of hit or miss you get enough antibiotic in there?
JOHN THORSON: Well, the fundamental mechanism and the reason why most antibiotics work is they have a mechanism that specifically targets machinery in the target bacterium and don’t have any effect on human processes, right? That’s what gives you the safety, that gives you the effectiveness of these types of molecules.
IRA FLATOW: Mm-hmm. And John, why is a bacterium– well, let me ask either one of you. Why is it so hard? Why are they so strong at resisting? What’s going on inside the bacterium that’s so strong in resisting these drugs?
JOHN THORSON: Well, bacteria, they have a– go ahead.
KIM LEWIS: So there are two aspects to this. One is that bacteria very rapidly acquire resistance. So if, let’s say, you have a wonderful drug that hits a particular protein, then that is going to mutate and your protein is not going to bind the antibiotic any longer. So our best antibiotics like penicillin, for example, they bind several related targets. But if you’re developing a new compound that binds only one target, then that will be a problem.
And the other very big problem is penetration. So bacteria evolved the terrific penetration barrier, their cell envelope, that restricts penetration of compounds that look like drugs. So some antibiotics, of course, are evolved molecules that evolved to penetrate, but we still do not have a very good understanding of which molecules will and which will not penetrate.
IRA FLATOW: Now, Kim, I understand the bacterium have like pumps. They just pump out the stuff once they get in there, right?
KIM LEWIS: That’s right. So those compounds that leak through this barrier of permeability, then those will be picked out by pumps and pumped out. And the pump will recognize chemically-unrelated compounds. That was a big surprise for us when we found such pumps.
IRA FLATOW: What about the idea of instead of killing the bacteria we trigger our own immune system to do that for us, Kim?
KIM LEWIS: Well, in principle, that is a good idea. That’s a promising direction. But our immune system is enormously complex, of course. The immune system, as you know, Ira, if you over-excite the immune system, you’re going to get either septic shock or auto-immune conditions. So it’s a very dangerous tool. We really need to know what we’re doing to do that.
But another aspect of that is, of course, vaccines. Well, vaccines have been around for a long time. Vaccines and therapeutic antibodies are the things that we are using right now.
IRA FLATOW: Mm-hmm. And so what about, John, about new ideas about how we could administer antibiotics differently? Could we give them differently?
JOHN THORSON: Well, I think one could take a lesson from the approaches we’re taking in anti-viral therapy, and that would be to combine drugs with different mechanisms. One of the points that wasn’t addressed previously is that bacteria rapidly grow, and that contributes to the resistance mechanism.
And so when you put them under selective pressure, they have a way to– you know, you kill off a large portion of the organisms, but there is a small population that has mutated to get around a particular drug. But if you’re hitting them with multiple agents at one given time, that could be advantageous.
IRA FLATOW: All right. Well, there’s a lot more to talk about with Kim Lewis, director of Anti-microbial Discovery Center at Northeastern, and John Thorson, director of the Center for Pharmaceutical Research and Innovation, University of Kentucky in Lexington. If you want to join us, please. Our number, 844-724-8255. And Twitter– you can tweet us @scifri. We’ll come back and talk lots more about this after the break. So stay with us.
This is Science Friday. I’m Ira Flatow. We’re talking about the science behind discovering and developing new antibiotics with my guests Kim Lewis at Northeastern University, John Thorson, University of Kentucky in Lexington. Now, to develop and distribute a new drug takes a lot of money. To find new antibiotics, we may need a new way to put money behind these drugs.
There is a small government agency called Biomedical Advanced Research Development Authority– we’ll call it BARDA– which came together after the anthrax attacks in 2001. The agency is taking a different approach when it comes to funding. Joe Larson is director of BARDA at the US Department of Health and Human Services in Washington. Welcome to Science Friday.
JOE LARSON: Thanks for having me.
IRA FLATOW: Would it be fair to say that BARDA is sort of the DARPA for antibiotics?
KIM LEWIS: You could say that. I think another way to put it is that we’re almost like a government-backed investment firm who makes investments in products that help us deal with public health emergencies on behalf of the American public.
IRA FLATOW: Ah ha. So the agency started CARB-X which is like an X-prize for antibiotics. How does that work?
KIM LEWIS: So CARB-X is a novel– basically a global innovation fund that we established to promote innovation in anti-bacterial drug, vaccine, and diagnostic development. And you know, what we recognized was that this is a global problem that has a very far reach. And in order for us to be able to adequately address it, we needed globally coordinated solutions.
And so CARB-X brings together two funders of biomedical research in the US, BARDA, as well is the National Institute for Allergy and Infectious Diseases. And it also forms a trans-atlantic partnership with the Welcome Trust, which is one of the premier funders of biomedical research, both in the UK and in the EU. And together, we’ve pooled resources to be able to invest, basically, $450 billion projected over the next five years at developing early stage antibiotic candidates so that they’re able to enter into clinical development.
But in addition to just providing funding, we also have put together a network of life science accelerators that, in addition to providing funding and technical support, also provide business and entrepreneurial support to help these kind of early stage startup companies become more sophisticated enterprises.
IRA FLATOW: So you sort of have a private-public partnership raising this money, from the government you and from venture capital firms, to get the research funded, I mean, the basic research. What areas most concern you now, and where you’re looking to fund?
KIM LEWIS: Right. So our model is innovative public-private partnerships, and we started this program back in 2010. Since then, we’ve supported nine different companies. We’ve been able to advance six different candidate antibiotics into Phase 3 clinical development. Our first BARDA-supported antibiotic candidates are projected to enter into the market into 2017, as well as 2018.
Historically, the way that we’ve invested is we invest where there’s the greatest unmet medical need. And to date, right now that’s gram-negative bacterial infections, which are these type of superbugs that you described before. Many of our products that we’re developing are analogs of existing antibiotics that overcome the known resistance mechanisms.
And through our investment through programs like CARB-X, we’re hoping to inject some new innovation and some new ideas for new and novel antibiotics, because, to be frank, there is a significant dearth of innovation in this space. And you ask the question is this really harder? It is harder from a technical perspective. But the underlying basis behind that is really an economic problem.
IRA FLATOW: Kim Lewis, what are your thoughts about– would BARDA have helped you?
KIM LEWIS: The short answer is no. Although of course it’s terrific that there is money being poured into this general area, and I’m sure that BARDA supports useful work. But having said that, I participated in several of workshops. One was called by the National Institutes of Health, the other by Pew Charitable Trust, where a group of experts were asked to identify the bottleneck in the overall process of developing an antibiotic.
And there was a consensus, a rare consensus– the bottleneck is not in development. The bottleneck is in discovery. We do not have enough leads to develop. So first, we need to figure out how to discover new antibiotics, and then there will be things to develop. So I would really be hopeful that the money will be put into discovery.
And there are very specific science challenges and gaps that we identify that need to be solved to provide us with a long-term solution to the problem of discovering new antibiotics, such as figuring out the rules that govern the penetration of molecules in the bacterial cell, or how to better access antibiotics or monocultured bacteria and the silent operands that they harbor, where the genes code for antibiotics but we cannot easily turn them on in the lapse. And these are some of the examples that we identified as key areas, where investment would be very helpful.
IRA FLATOW: John Thorson, where do you think the major bottleneck is developing new ones, new antibiotics?
JOHN THORSON: I think– so I agree with Kim that investment in discovery is an important component. I believe that also on the academic research side, we have to be realistic about thinking once you discover a molecule, you have a putative hit. You have to advance that to a certain component, and not all academic research labs, or even institutes, are sort of set up in thinking in that regard.
You know, the end goal here is to position a potential early stage lead for support by a program like BARDA so that you can put together a compelling data package that says these molecules have suitable in-vivo properties and show suitable efficacy in an animal model. And you can really lay out a case that if a funding agency like BARDA were to invest, it’s going to have legs to actually get to the point of entering into the clinic.
IRA FLATOW: Joe Larson, we’ve talked many times about how expensive it is to get a drug to market, and one of the great bottlenecks– or is the resistance by drug companies to make new antibiotics because they are expensive to test also? How do you get through that bottleneck? $400 million in your budget might be good for the basic research, but it’s not going to get $100 million clinical trial going.
JOE LARSON: Right. Well, a lot of the work that BARDA does is actually supporting the clinical development of these molecules. And so as I mentioned, we’ve advanced three of these programs into Phase 3 clinical development. We are supporting the cost of those trials to help get these products into the market. But it’s important to note that all that we’re doing is we’re lowering the R&D costs of these companies to be engaged in this space. And that basically is keeping the companies that have remained in developing antibiotics at the table doing that.
If we really want to promote innovation in this space, if we really want to fix the market failure for antibiotics, we need to be rewarding the innovation that comes with bringing a new antibiotic to market. And we need a totally different market models for the ways that we incentivize this industry base to want to participate in this.
You take the last six antibiotics that were FDA approved and project– the first two years of projected sales ranged between $30 to $80 million. And that may sound like a lot of money, but if you put that toe to toe with drugs like Lyrica for diabetic nerve pain, or Spiriva for the treatment of COPD, their first two years sales were in excess of a billion dollars, or approaching $750 million. And so if you’re a private investor, you know, which company are you going to invest in– the company that’s developing the billion dollar blockbuster, or the company, the antibiotic company, that may make $40 million in its first two years?
And so we need to be rethinking the way that we reward these companies, and the way to do that is ensure that we have a market model that rewards innovation, promotes conservation of these products, and then also allows access to the patients that need these products when they’re experiencing a drug-resistant infection.
IRA FLATOW: With the new administration in a cost-cutting mood, do you think that BARDA is going to survive in the next budget round?
JOE LARSON: Well, we have a lot broader of a mission space than just antibiotic resistance. We deal in protecting the American public from mass public health emergencies, and that involves bioterrorism agents. It involves pandemic influenza. It involves emerging infectious diseases like ebola and Zika. And you know, I hope that Congress and the American public view our role as a pretty critical one to keeping our nation safe and would want to sustain that investment. And we’re hopeful that that’s the case.
IRA FLATOW: We’ll find out. Budgets are coming up in the next few days. Thank you, Joe Larson, director of biomedical advance research development at the US Department of Health and Human Services, Kim Lewis, director of the Anti-microbial Discovery Center at Northeastern University, John Thorson, director of the Center for Pharmaceutical Research and Innovation, University of Kentucky in Lexington. Thank you for taking time to be with us today.