Looking To Nature For Antibiotic Inspirations

Apr 12, 2013
Originally published on April 12, 2013 12:03 pm



This is SCIENCE FRIDAY. I'm Flora Lichtman. Later in the hour, a teenage science activist and the plight of the monarch butterfly. But first, researchers have developed a new way to fight antibiotic-resistant microbes by borrowing a trick from a longtime foe of the bacteria, the bacteria phage.

Phage are viruses that infect bacteria, and they sort of look like alien space probes: tall and thin with a bunch of legs, or technically tail fibers coming out the bottom. Recording in PLOS One, the researchers describe a new antibiotic that channels some aspects of phage warfare.

They found it works on bacteria that don't respond well to conventional antibiotics, bugs like MRSA, an antibiotic-resistant form of staph. And joining me now to talk about the work is the lead author in the report, Vincent Fischetti. He's a professor in the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller University here in New York. And you may recall him as SCIENCE FRIDAY's go-to expert on the topic of eggnog food safety. Welcome back to the show, Dr. Fischetti.

VINCENT FISCHETTI: Thank you, Flora.

LICHTMAN: I'm so glad we talk to on the eggnog offseason to hear...

FISCHETTI: Yes, on real science.


LICHTMAN: Well, it's a matter of opinion there.

FISCHETTI: Right, right.

LICHTMAN: So tell us about how this works. What tricks did you borrow from the phage?

FISCHETTI: Well, you know, the holy grail in antibiotic development is the target, the molecule, which the antibiotic is inhibiting. And we're really good at identifying molecules that kill bacteria, but we're really not good at identifying which molecules the bacteria can't get around or become resistant to. And the phage are really good at this.

They've been hanging around with bacteria for about a billion years, and they - in order for them to survive, they need to know what bacteria can change and what they can't. And during this billion years they've identified some very interesting molecules that bacteria can't really circumvent. So we've taken advantage of that.

LICHTMAN: So this is - it's like an arms race. Right, yeah, it's an evolutionary arms race, but we're going to hop in and take advantage of what these phage have figured out.

FISCHETTI: Right, exactly. So they've been looking at and probing bacterial molecules for a billion years, and they've identified a few interesting ones. And we've selected one of these as a proof of principle to see if this would work, and we identified an antibiotic that would block that molecule, and that antibiotic will kill gram-positive organisms and also resistant gram-positive organisms.

But the most interesting thing is when we test for resistance, we cannot find resistant organisms. It goes beyond our method of testing. So it's less than 10 to the minus 11th frequency, which is the maximum level that we could test at.

LICHTMAN: Wow. So how does it work exactly? What's the mechanism?

FISCHETTI: Well, the molecule is really a molecule in the cell wall of the bacteria that the organism, the bacteria, would have to remodel its whole cell wall in order to make this particular structure again, and it's very difficult to go through that manipulation. And the phage have figured this out, and we just took advantage of this molecule.

LICHTMAN: So your compound inhibits the production of this molecule that's important for the cell wall?

FISCHETTI: Exactly. It inhibits the pathway for the synthesis of this critical molecule.

LICHTMAN: When you look at the pictures in your paper, after it's - after I think, for instance, anthrax bacterium has been exposed, it gets these raggedy edges around the cell wall.

FISCHETTI: Yeah, these are treated with sub-lethal doses of the compound. And therefore they can't synthesize their cell wall properly. So they look really gnarled, the cell wall is really thick. They're very, very ill organisms. So they cannot grow properly. So all you need to do - and that's at sub-lethal doses. You add a little bit more of that compound, and the organisms just cannot survive.

LICHTMAN: Have - you've tested this on the anthrax bacterium and MRSA. Have you tried other bacteria, too?

FISCHETTI: It works very well against most gram-positive organisms. So these are the staphylococci, streptococci, pneumococci. We don't see any effect on gram-negatives, but we think now that it's because the compound can't get through the outer membrane of gram-negatives.

So the molecule is now being re-engineered hopefully to be able to kill not only gram-positives but also gram-negatives.

LICHTMAN: Have you tried this out in people?

FISCHETTI: Not yet. We can't do that until we've gone through safety studies.

LICHTMAN: What's the timeline?

FISCHETTI: Well, like most compounds of this sort, it would take probably this year before we do all of our analyses and safety studies. I think with phase one, phase two and phase three maybe five to six years.

LICHTMAN: Are you using any other tricks from the phage?

FISCHETTI: We're using things from phage to kill bacteria outright. We're using enzymes that phage produce to actually kill bacteria. These enzymes are used by the phage to get them out of infected bacteria. And we're working with a company that has now engineered these molecules to be used to kill organisms, as well.

LICHTMAN: These are the molecules that actually cause the cells to cleave apart. Is that right?

FISCHETTI: The life, exactly. What happens is the bacteria phage infect the bacterium. They take over the cell for the production of new virus particles. And within 45 minutes to an hour, the phage have to get out of that bacterium to release their progeny, to infect other bacteria.

And they solved the problem by producing an enzyme that punches a hole in the cell wall, and the bacteria explode, releasing their babies out into the environment again. And what we've done is just purified that molecule and actually can use it externally to kill bacteria virtually instantly.

LICHTMAN: Wow, are those molecules bacterium-specific?

FISCHETTI: In some cases they are. In fact, we - in most cases they are. We actually just found a molecule that is actually being developed for phase one clinical trials that will kill a number of different gram-positive organisms. So it's actually our broadest-acting enzyme.

LICHTMAN: Why not use phage generally? Why just take their tricks? Why not employ them to do the task?

FISCHETTI: You know, when - before antibiotics were discovered, phage were a possibility of a way of controlling bacteria. But since antibiotics came in, we start using antibiotics. One of the problems with phage is that bacteria become resistant to the phage very rapidly. So in order to kill a particular organism, you need to make a cocktail of several phage in order to kill that one organism.

So you become - you're dealing with a very complex mixture, and FDA really doesn't like complex mixtures. So it - they work, but they're difficult to really produce in large quantities. It's a lot - homogeneity is a requirement by FDA. So I think even though they work, it's a large hurdle for them to go over in order to get these out into the public.

LICHTMAN: Let's go to the phones, Caroline(ph) in Anchorage, Alaska. Welcome to the show.

CAROLINE: Thank you so much. I was curious as to the origin of this study. I thought I remembered reading somewhere that it was after World War I that the Russians started down this path of inquiry. And I was curious if that was correct. And this sounds like a wonderful visual that could be used to get young kids interested in science because you've got one thing firing off and destroying another, and that's always kind of a fun to thing to look at if you're three or four years old.

FISCHETTI: Phage are wonderful to work with. Lots of children work with phage as a first experiments because they give you plaques, they give you, you know, holes on bacterial lawns. They're easy to isolate. And every one you isolate is different. There are 10 to the 31 phage on Earth. So if you isolate a phage from the soil sample or water sample, it is unique. There is nothing like it anywhere else because they are very, very unique. No one will ever isolate the same phage twice.

To answer your question, yes, the Russians were one of the first people that were involved in phage therapy, and when antibiotics came in, the Western world went into antibiotics, and the Russians stayed with phage therapy. And there are institutes in Tbilisi that if you go there now, you could be treated with phage.

If you have a diabetic foot ulcer and it's untreatable here in this country, hopefully they'll find a cocktail of phage that will cure those ulcers.

CAROLINE: That would be good because we're having repercussions from all of the antibiotics in our environment.

FISCHETTI: Yes, I mean, they won't solve all the problem, but they will solve very difficult, highly resistant problems where certain infections cannot be treated by any other means. And phage therapy can work in certain instances. But it's boutique treatment. They have to make a cocktail for the organism that is causing your infection.

LICHTMAN: Thanks, Caroline.

CAROLINE: Thank you.

LICHTMAN: Could you take the molecule that you reported this week, in PLOS One, and put it into a gel, like a hand sanitizer?

FISCHETTI: I'm sure you can. You wouldn't want to do that.


FISCHETTI: That wouldn't - I mean, I think you - the more - again, even though we don't see resistance for this molecule, the more you expose organisms to these types of molecules the more chance they have to be exposed to them and start to become resistant. So even though we don't see resistance, you want to limit the use of these types of compounds to infections that really need to be treated.

LICHTMAN: I wondered if you could design, based on phage, particular antibiotics that really went after particular bacteria so that you wouldn't have to clean out your entire gut or whatever using a broad-spectrum antibiotic.

FISCHETTI: Yeah, that's a very good point because right now what pharmaceutical companies look for are broad-spectrum antibiotics. And the reason for that is when someone comes into the hospital, we don't really know, or the physician doesn't really know, what is causing the infection. So they want to treat with an antibiotic that will kill a number of different types of organisms.

What we really need are diagnostics that will tell you as soon as you walk into the hospital what organism is causing the infection, and then you can use a very specific antibiotic to kill that organism. And that way you avoid the whole problem of killing lots of organisms, which are really necessary for health and well-being and cause other problems when you start destroying your normal flora.

LICHTMAN: That's about all we have time for, Dr. Fischetti. Thank you so much for joining us today. It was a pleasure to get to talk to you.

FISCHETTI: My pleasure, thank you.

LICHTMAN: Vincent Fischetti is a professor in the Laboratory of Bacterial Pathogenesis and Immunology at Rockefeller University here in New York. And travel over to our website to see Dr. Fischetti on a labor of love from his lab, eggnog. We've done some experiments with him in the past, get you ready for that Christmas season, it comes earlier and earlier. Stay with us.


LICHTMAN: This is SCIENCE FRIDAY, and I'm Flora Lichtman.


LICHTMAN: This is SCIENCE FRIDAY, and I'm Flora Lichtman. Transcript provided by NPR, Copyright NPR.