Antibiotic Resistance A Major Medical Challenge Antibiotic resistance is one of the major threats facing todays's modern medicine. Richard H. Ebright, a chemistry professor and researcher, explains new approaches for developing antibiotics that may lead to methods for treating drug-resistant tuberculosis and other diseases.
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Antibiotic Resistance A Major Medical Challenge

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Antibiotic Resistance A Major Medical Challenge

Antibiotic Resistance A Major Medical Challenge

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This is Talk of the Nation: Science Friday. I'm Ira Flatow. A little bit later, a new opera about the atomic bomb. But first, back in the 1940s, the microbiologist Selman Waksman discovered streptomycin, the first effective antibiotic against tuberculosis. He went on to win the Nobel Prize for his discovery. But today, almost every bacterial infectious disease has a drug-resistant strain, including tuberculosis. And to find new antibiotics to fight these drug-resistant strains, scientists are turning back to soil samples where streptomycin and many other antibiotics were found.

They've had some very successful luck in identifying new antibiotic compounds and figuring out how they work. Some of these may even help to fight against drug-resistant tuberculosis today. Joining me now to talk about that research out today in the journal Cell is my guest Richard Ebright, investigator for the Howard Hughes Medical Institute. He's also a professor in the department of chemistry and chemical biology at Rutgers University and laboratory director at the Waksman Institute of Microbiology there in Piscataway, New Jersey. He joins us from New Jersey. Welcome to the program, Dr. Ebright.

Dr. RICHARD H. EBRIGHT (Waksman Institute of Microbiology, Rutgers University): Thank you very much. Good afternoon.

FLATOW: Tell us about these antibiotic compounds. They come from the soil?

Dr. EBRIGHT: That's correct. We studied three compounds. The three compounds were identified by our German collaborators, Rolf Jansen and Herbert Irschik, by screening soil samples. They screen soil samples from microbes that produce antibiotic compounds, compounds that are effective against other microbes in the soil environment. Microbes produce these antibiotic compounds as part of their competition for scarce nutrients in the hostile nutrient-foreign environment of soil. Scientists are able to exploit this by identifying microbes that produce such compounds, isolating, characterizing and developing further such compounds.

FLATOW: So, the bacteria fighting each other in the soil?

Dr. EBRIGHT: Correct.

FLATOW: And it's a survival-of-the-fittest bacteria, and they put out these poisons. They try to poison one another.

Dr. EBRIGHT: Correct.

FLATOW: And you find those antibiotics. Are these new bacteria - are these new antibiotics, or have we known about them before?

Dr. EBRIGHT: Our collaborators, our German collaborators, identified the three compounds we analyzed nearly two decades ago. So, they've been known and they have antibiotic activity, but they're not ready in their initial form for the clinic. In order to bring them to the clinic, their potency has to be optimized. They have to be made more potent. The pharmacological properties have to be optimized. In order to do that in a rational and informed way, we need first to define their target, their mechanism of the action, and the structural basis of their mechanism of action, and that is what we have now done.

FLATOW: And what makes them unique in that sense?

Dr. EBRIGHT: What is special about these is that their target, their biological target inside a bacterial cell, is the molecular machine that the bacterium uses to carry out its first step in gene expression. In this step in gene expression, the genetic information stored in DNA is read out and synthesized as a copy in RNA. The molecular machine that carries out this critical first step in gene expression is called RNA polymerase. It's a protein machine. It is a large protein machine. It has dimensions on the nanometer scale and has multiple moving parts.

The importance of this target, in terms of antibacterial therapy and anti tuberculosis therapy, is that this machine is essential for survival of a bacterial cell. If one inhibits this machine, a bacterial cell dies. This is a proved target for broad-spectrum antibacterial activity. That means antibacterial activity against many different species of pathogens. It is a proved target for broad-spectrum activity because all species of bacterial pathogens have this machine, and they have versions of this machine that are sufficiently similar to drugs that target the machine from one species of pathogen, and also are successful in targeting the machine in other species of pathogen.

FLATOW: So, you're basically targeting that machine inside?

Dr. EBRIGHT: Correct.

FLATOW: You're, like, throwing a monkey wrench into it?

Dr. EBRIGHT: Correct, and again, it has been approved target for broad-spectrum antibacterial therapy, but in particular, it is a uniquely important critical target for anti-tuberculosis therapy. The reason for that is that in a patient with active tuberculosis infection, there are both rapidly growing tuberculosis bacteria and slow-growing tuberculosis bacteria. The slow-growing bacteria are called persistors. In order to clear the infection and cure the patient, one needs to kill both types of tuberculosis bacteria, the rapidly growing ones and the persistors. In the persistors, there are very few biochemical activities occurring in the persistor cells. And as a result, there are very few points of vulnerability.

There are very few ways that the drug can interfere with the survival of a persistor. There is one clearly known proved target to kill a persistor, and that target is the machine that we've been studying, bacterial RNA polymerase. The persistors need RNA polymerase to survive. If one interferes with the activity of RNA polymerase in the persistor, the persistor dies. As a result, this enzyme, this machine, bacterial RNA polymerase is uniquely important target for anti-tuberculosis.

FLATOW: Now, I'm trying to visualize a real machine here. Give me an analog of what actually in that machine are you aiming for.

Dr. EBRIGHT: So, this is a machine with moving parts. Perhaps the simplest way to envision this machine is to imagine a crab's claw. This machine has a shape reminiscent of a crab claw with two prominent pincer-like projections and a cluster between them. When this machine functions, it must grab onto DNA, just like a claw, grabs onto an object, grabs onto food, for example. To do that, the claw must open to be able to bind DNA, and then must close to be able to hold on to DNA. This opening and closing occurs by a swinging motion of one of the two pincers of the claw about a hinge added space. What we have found is that these three compounds function by binding to that hinge and jamming it. They jam at it in a closed state, so that the claw can't open to bind DNA. Since it can't open to bind DNA, the machine can't function. Bacteria can't live.

FLATOW: So, it's like putting one of those rubber bands around the lobster claws we see.

Dr. EBRIGHT. In a way, that would be a way to describe it. Putting gum in a hinge would be another way to describe it. Putting sand in a hinge would be another way to describe it.

FLATOW: Would these bacterium not find another way to mutate and go around this sort of mechanism?

Dr. EBRIGHT. For any bacterial compound, resistance ultimately is inevitable. Bacteria are able to mutate to overcome this attack. They are able to develop resistance to these agents. What needs to be done, therefore, is to administer agents developed from the compounds we've studied in a responsible fashion, in combination with other agents. This is routinely done in anti-tuberculosis therapy. Combination therapy prevents the emergence of resistance if it is done responsibly and correctly.

FLATOW: So, how soon do you think we'll have a working drug?

Dr. EBRIGHT. What we have now are what we would refer to as lead compounds. There are compounds that exhibit broad-spectrum activity against many bacterial pathogens, including the tuberculosis bacterium. They have high potency against many bacterial pathogens including the tuberculosis bacterium. One of them has no toxicity in animal tests, even when tested at high levels. For that compound, we now know exactly how it interacts with its target. We know which atoms of the compound interact with which atoms of the target. We are able, therefore, to predict changes to that compound, changes to which chemical structure that would increase its interactions with the target, increase its binding affinity, increase its potency and make it more effective.

We have a means of synthesizing that compound. We currently are synthesizing analogs, or derivatives, of the compound intended to have higher optimized potency. Thus far we synthesized about a dozen, synthesized and tested them, all were active. We plan to greatly expand our program of synthesis and testing, and we hope that within a time frame of perhaps one year, to perhaps two to perhaps three years, we will have identified compounds that have significantly increased potency and optimized pharmacological properties in a position to enter into clinical trials.

FLATOW: With so many bacterial infections and these diseases of drug resistant strains, I would imagine there's got be a lot of money going into this field.

Dr. EBRIGHT: There are funds, but there is also a great need. The pharmaceutical industry has largely left this sector. The pharmaceutical industry, during the '80s and '90s, moved out of anti-infectives and in particular out of the anti-bacterial agents, seeking other areas of higher commercial promise. And in part because of that movement of the pharmaceutical industry away from the sector, the pipeline of new antibacterial compounds, genuinely new compounds from new chemical classes, like the compounds we've been discussing, is very, very dry.

FLATOW: So, they've gone to the big, gross-producing, popular drugs like the statins and things like that?

Dr. EBRIGHT: The key difference between an anti-infective and the statin is that an anti-infective is given for a short period of time, or relatively short period of time. A patient is ill. The patient takes the anti-infective compound perhaps for one week, perhaps for two weeks. For most infections, the patient is cured. In contrast with the statin, the patient goes on it and is on it for life. That gives a longer term market, and the business side of the pharmaceutical industry has chosen, I think, unwisely, to focus on that potential longer term market, and has tended to neglect the area of anti-infectives.

FLATOW: Well, if you come up with a good anti-infective, how could you then get it distributed if they are not in that business anymore?

Dr. EBRIGHT: The pharmaceutical industry is - understands that there is a need - understands that they can produce these compounds and market them and sell them at a profit. What they have left, what they've abandoned, by and large, is the development stage. If one can identify compounds - lead compounds, such as the once we've been discussing with excellent antibiotic properties - if one can define their targets, their mechanisms, their structural basis of interaction and then can use that information to optimize those compounds, bringing the development stage all the way up to clinical trials, then the pharmaceutical industry is willing to take over.

FLATOW: But in the meantime, you have to find your own money from someplace else?

Dr. EBRIGHT: That's right. So, one finds resources from the funding agencies that support basic research, for example, the National Institutes of Health, which provided major funding for this work, the Howard Hughes Medical Institute, which provided major funding for this work, the Helmholtz Institute in Germany, which provided funding for this work. And one seeks additional resources from other basic science and transitional science and translational science funders such as the Global Alliance for TB Drug Development.

FLATOW: Well, thank you very much, Dr. Ebright, for taking time to be with us, and good luck in finding that drug.

Dr. EBRIGHT: Thank you.

FLATOW: Richard Ebright is an investigator for the Howard Hughes Medical Institute, and he's a professor in the department of chemistry at Rutgers University. We're going to take a short break and switch, and come back and talk about an experiment that was done well over 50 years ago. And science, has it gone back? And look at the residue left over and, wow, found a lot of stuff that was missed back then. So, stay with us. We'll be right back after a short break.

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