Hitting The 'Off' Switch On Antibiotic Resistance

Doctors are running out of effective antibiotics, as bacteria evolve ways to evade one drug after another. Now DARPA has called for alternatives to conventional antibiotics. Nanotechnologist Chad Mirkin discusses one such weapon—tiny globs of DNA and RNA that can switch off the bugs' antibiotic resistance. Nanotechnologist Chad Mirkin discusses next-generation antibiotics that target a bacterium's DNA.

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IRA FLATOW, HOST:

This is SCIENCE FRIDAY. I'm Ira Flatow. In the battle of antibiotics versus bacteria, the bugs are winning. Not only are they evolving resistance to our arsenal of drugs, but we're running out of new antibiotics to launch at them. And antibiotic-resistant bacteria aren't just a problem for hospitals and patients. Think about wounded soldiers on the battlefield, infected with superbugs or a bioterrorism attack using resistant or engineered pathogens.

Would we be able to handle it? That's why DARPA, the research arm of the Defense Department, has called on scientists to develop new, next-generation antibiotics. One promising technology is DNA-based drugs that not only target the superbugs, but they can evolve right along with them, preventing antibiotic resistance.

Chad Mirkin is director of the International Institute for Nanotechnology at Northwestern University in Evanston, Illinois. Welcome back to SCIENCE FRIDAY, Dr. Mirkin.

DR. CHAD MIRKIN: It's a pleasure to be here.

FLATOW: These are little nanoparticle-sort-of-sized things?

MIRKIN: Yeah, they're really interesting structures. In fact, they're structures made out of DNA or RNA that are made on a gold nanoparticle, in fact a variety of different types of particles, but they're strands of DNA that are arranged on the surface of these spherical particles.

And when you make them in this manner, they have properties that are very different from the normal type of DNA that we're all familiar with, duplex, linear type of DNA, and one of those properties is they have the ability to enter cells, including bacterial cells, very, very efficiently.

FLATOW: And when they get in the cell, what do they do?

MIRKIN: Well, the beauty is what we can do. We can design them so that they can go in and flip switches, genetic switches, that either turn off resistance so that a conventional antibiotic will work or, better yet, stop replication and ultimately cause bacterial cell death.

FLATOW: So is there then no need for a standard antibiotic?

MIRKIN: Well, this would be a different route to the standard antibiotics, which are typically small molecules. This would be a genetic-based route, and the beauty of that is that, as you said in your opening, you can move with the bug. If the bug evolves, you can change the sequence and target different genetic components of the bug so that you can constantly battle its response to the new drug.

FLATOW: So as the bug changes, you tailor-make the new stuff to mimic what the bug is doing.

MIRKIN: That's the idea. I mean, this is very early in this whole process. This is actually part of a big platform that we call spherical nucleic acids that we've been developing at Northwestern now for about 15 years and are part of a company that we started called Aurasense that can really go after any sort of genetic disease.

And that's the beauty of it: You can tailor it on a disease-by-disease basis, as long as you have good genetic information about the different types of switches that you have to turn on or off to effect treatment.

FLATOW: If you have - then if you have genetic diseases that are not, you know, antibiotic-related, maybe like cancer or something like that, could you not go in and stop the cancers from spreading that way?

MIRKIN: That's exactly right. In fact, we have a very active program in that regard. The beauty of these constructs, they're part of a larger field called gene regulation, which actually has won the Nobel Prize for its promise, the idea that you could use this - a concept of switching off genes or down-regulating genes so that you could adjust protein levels and take effectively a diseased cell and make it healthy, or in the case of a cancer cell, selectively cause it to die.

The problem with conventional approaches is that they often have to have materials to help carry the genetic material into the cells, and they're not very good at targeting. In addition, they cause all sorts of toxic side effects. So you run into the problem where the therapy causes as many problems as the disease originally did.

In this case, these structures, this kind of spherical form of nucleic acid, has this incredible property that it requires no co-carrier. You can treat diseases based upon that genetic information, and you can either locally deliver - for example we have projects with a dermatologist named Amy Paller, where we have the first constructs that can be delivered through the skin to go after things like melanoma and psoriasis.

Or another project involves a guy named Alex Stegh, where we're going after brain cancer, and we can systemically deliver these. They go everywhere, but they cause no toxic side effects, and so they accumulate in a lot of cells, including tumor cells in the brain, and you can selectively go after those cells based upon the genetic differences of those cells causing them to selectively die.

FLATOW: So even though they get into the cells, their little genetic pieces don't match up with the wrong cells then?

MIRKIN: That's exactly right. You've got almost a lock-and-key type of shutoff here.

FLATOW: You know, there are a lot of people who were concerned about pumping a bunch of nanoparticles into their body, and I guess they would be concerned about this, too.

MIRKIN: Well, potentially. I mean, the interesting thing about this is, so typically, we will use a gold particle, and we'll arrange the nucleic acid, the DNA or RNA on the surface of the particle. And that itself can be a therapeutic, and we have a lot of therapeutic leads based upon those types of materials.

But we've also figured out ways of what's called cross-linking, attaching the DNA strands on the surface of the particle to each other, and we can dissolve the gold, and we literally can use effectively pure nucleic acid in that case. And those types of constructs work just as well.

FLATOW: All right, now for the $64 question, which I know you knew would be coming, right? You could probably ask it of yourself: When are we going to have a product that is going to be available to try?

MIRKIN: Well, I think the more important question to ask is when are we going to go into trials. So we have incredible in-vivo data in animals, small animals, that suggests that this works and works extremely well. And it can do things that frankly no other gene regulation construct has ever done before, and that is delivery through the skin, very effectively, knock-down in animals, and also this idea of systemic delivery.

And what's really difficult in this field is getting these big drugs - because they're big particles compared to the small-molecule drugs that we've been talking about - getting them across the blood-brain barrier. And the beautiful thing about these constructs is they show the ability to do that.

And so the real question is how soon will we be into trials? And we're really shooting for next year. So we're hopeful that we're going to be into human trials sometime next year, pushing for the early part but certainly before the end of the year.

FLATOW: And as far as antibiotics are considered, do you consider them old hat now?

MIRKIN: No, I wouldn't consider them old hat. I mean, this may end up being a co-therapy, or it may be a replacement for existing antibiotics. But a lot of work has to be done. So the DARPA program is actually new. It was, I think, really insightful for them to take this on and to challenge the community to come up with new ways because the world desperately needs these types of constructs.

We have to really go through and validate these in the context of bacteria, like we have in the context of diseases like cancer in small animals. And so what we're going to be doing over the next year on the bacteria side of things is really starting with cells and then moving up through bacteria and then animal studies.

FLATOW: And why is it that DARPA has to jump in here? What's wrong with our own medical system?

MIRKIN: Well, DARPA - I don't know if it's a matter of what's wrong. It's a matter of creating challenges. And so there are business challenges, and one of the problems, of course, in the antibiotic area is that from a drug standpoint, they're not nearly as big a market as, for example, an oncology type of drug.

But there are also just challenges in - grand challenges in terms of chemistry and material science that have to be overcome, and you have to get a lot of different folks together to solve big problems. And DARPA is extremely good at doing that.

They move very rapidly when they recognize you have a big problem. They're able to first of all put together substantial resources, which is needed in this case, to challenge the academic community in this case to come up with alternative solutions and to think outside of the box. And they're one of the best agencies for doing that.

FLATOW: So what you're saying is that the people are willing to spend money on the military to do this where they might not in a civilian case.

MIRKIN: Well, yeah, the military has a different set of drivers, right. So they're not...

FLATOW: So where we used to think of the military as making weapons and transistors and things, they're now making drugs.

MIRKIN: They make a lot of things. They made our GPS, as well. They make a lot of things that positively affect civilians in day-to-day life, and this would be a big one.

FLATOW: All right, thank you very much, Dr. Mirkin, for taking time to be with us. We'll have you back on when you get some results, when the trials begin.

MIRKIN: Thank you.

FLATOW: Chad Mirkin is director of the International Institute for Nanotechnology at Northwestern University in Evanston, Illinois.

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