Reply To: Dr. Vince Fischetti – Microbiologist (Video & Excerpt Available)

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    The following was excerpted and edited for clarity from the on-camera interview.

    Question: Your lab is focused on bacterial pathogenesis and immunology. Tell us about your current research.

    Answer: Right now we’re doing several things. One is to look at phage lytic enzymes as a means to control infection or prevent infection. We’re also looking at vaccine development for Group A strep and trying to understand how molecules attach on the surface of gram-positive bacteria; to inhibit their presentation on the surface. Naked bacteria can cause infection, and that would be a novel way to control bacterial infections. And also, we’re looking at novel antibiotics and novel pathways to identify new antibiotics. So we do a variety of things.

    Question: Professor, you’ve researched streptococcus for more than four decades, which seems like an amazing commitment. Is that because that’s an amazing microbe? And how is your understanding about this microbe evolved?

    Answer: I started here as a technician in this laboratory over 40 years ago. And the projects were streptococcal-related, and I stayed with the project because it’s, it’s an organism that 40 years later still causes serious disease – and we have no vaccines or good ways of preventing infection from Group A strep. We can treat it once infections occur, but it’s very difficult to prevent these infections. And that’s really been the thrust of this lab, is to try to prevent infection…

    ….We’ve been interested in developing these phage lytic enzymes that will prevent infection; that is, to decolonize people of their pathogenic bacteria…at least 50% of humans carry pathogenic bacteria in their upper, in their upper respiratory tract…

    For instance, Group A strep, pneumococci, and staphylococci are colonized in the upper respiratory tract of humans and that’s their only reservoir in most instances. And those organisms will cause infection in the individual that is carrying those organisms. If you could eliminate them in some way, safely, you could eliminate a lot of disease. And, right now, there is no good way of eliminating these organisms specifically, and we’ve developed a method by which we can specifically eliminate these organisms from mucous membrane surfaces.

    Question: What is a biofilm, and how might they, how might they present problems to humans?

    Answer: Basically any bug can form a biofilm. A biofilm is just an accumulation of organisms at a particular site. These organisms secrete polysaccharides that cover them in a slime. There are channels in that slime. They can communicate with each other in that slimy surface and that is basically the biofilm. They don’t tend to grow very much once they’ve established the biofilm, which is one of the reasons why they’re difficult to treat.

    Question: Studies from the CDC say that up to 80% of chronic infections involve biofilms. What’s the connection between bacterial biofilms and chronic health conditions?

    Answer: They are very difficult to eradicate because they don’t grow rapidly, and most antibiotics kill organisms that are growing and they will not kill organisms that are not growing. So these organisms can fester in a particular area. For example, endocarditis is (caused by) a biofilm of organisms on the heart valve.

    … in diabetic foot ulcers, where organisms will colonize the ulcer, it’s difficult to eradicate those organisms. So, these are chronic conditions where organisms have become intractable and unable to be eradicated with just simple antibiotic treatment. They just don’t grow very well; the biofilms really cover them and prevent the antibiotics from getting in properly to give them a high enough dose to kill them. So, in a sense, (this is) a protective way in which these organisms can survive for long periods of time in a particular area of the body.

    Question: Are there any standards to characterize either mono- or polymicrobial biofilms?

    Answer: Well, as far as I know, the only way you can do that is to take the biofilm, break it up into its individual components and measure what organisms are in there and what percentages of those organisms make up the biofilm itself. Unless you can culture the organism, you won’t know what the comp-composition of that biofilm happens to be. And since about 90% of the organisms in our bodies are unculturable, we can have biofilms that are representative of organisms that will not grow under normal conditions, and they’ll be underrepresented when we look at the compositions. So they could be doing something to that biofilm, but we wouldn’t have any idea what it’s doing, since we can’t isolate that organism.

    Question: Studies from the ‘90s, or actually even the ‘80s report that certain antibiotics can actually cause microbes of all different types to change form. Does that imply that certain meds — whether it be antibiotics or other — can drive some microbes into a state of dormancy, only to have them reemerge, months or years later? Are these called cyst forms?

    Answer: As I mentioned earlier, organisms are more susceptible to antibiotics if they’re actively growing. If their metabolism slows down significantly, then they’re more resistant to the antibiotics. So what you’re doing is, when you’re treating with certain antibiotics, you’re killing the organisms that are growing. You select for mutants that are slow growers — and those are the guys that will be the persisters because you’re just selecting.

    Genetically, those organisms grow much more slowly and therefore they’re hiding out. There has always been a suggestion that when you treat gram-positives with penicillin, which causes an effect directly on the cell wall, that the cell wall falls off and you now have some resistant organisms — because they are called, (pause) cell wall-less organisms or L-forms. And then these L-forms can survive in the presence of an antibiotic because they don’t have a cell wall. How much latent infection that actually causes has been con- very controversial for decades.

    Question: How might microbes of all different kinds work together? For example, I think some of Dr. Bill Costerton’s early work suggested that gram-negative and gram-positive bugs might kind of work to cooperate to help each other survive. Can you comment on that?

    Answer: Well, I think all bacteria work together and in combination even with bacteriophage. I mean, you can’t forget that bacteriophage play a major role in all of this. We tend to ignore a bacteriophage, because they don’t cause human disease, but they really have a lot of control over the bacteria that they infect. And so you’re really dealing with gram-positives and gram-negatives. They produce a variety of different, secretory compounds that either will, will control their environment or stimulate the environment for certain purposes. I mean, they’re all there to survive and it’s a matter of what they produce and how they can live together in this environment — and it’s these molecules that allow them to interact with each other and live in a particular environment. So that’s absolutely true that they work together to survive in the body or anywhere else — in the soil if they’re soil organisms or on plants or what have you. They’re all working together to survive.

    Question: Are there any bacteria that are generally regarded as being the most sophisticated? For example, MRSA has demonstrated its ability to employ quorum sensing to detect neutrophils and perforate them with Phenol-soluble modulins. Are there myriad examples of clever defensive strategies and how does that gel with newer synthetic methods to eradicate them?

    Answer: Well, each pathogen has its own unique set of traits that allows it to cause infection. They either have surface molecules that allow them to attach to a specific site in the body and then they secrete molecules that allow them to invade. And then, once they invade, they have other molecules that prevent them from being killed by white blood cells, and a hole they just get through, a whole myriad of changes, and at different sites, and different periods in the infection cycle that allows them to survive. E. coli, for example, has sophisticated injection devices where they can inject molecules into a cell that they’ve attached to; control the cell, allow it to be taken in….and in very, very sophisticated ways in which these bacteria have been able to subvert humans and cause infection.

    What we have to do is learn how these things work and then try to circumvent those problems by killing them in a specific way to get around these very sophisticated methods. We’re using enzymes to actually slam ‘em on the head — basically, it doesn’t make a difference what they have that allows them to cause infection if we punch a hole in their cell wall and they explode. They’re dead, and they can’t go any further than that.

    Question: How does Strep pneumonia, pneumoniae cause something like meningitis or septic arthritis or even endocarditis? Can you maybe pick one of those conditions, and kind of walk us through the disease process?

    Answer: Well, endocarditis is just a good example of that. Endocarditis is an infection of the heart valve and it usually occurs when a person has a defect in the heart valve. It could be rheumatic heart disease, where the heart valve has been damaged because of a strep infection. So these defective valves can become colonized by any organism that enters your blood. One of the organisms that can enter your blood is Pneumococcus, because it’s found in the nasal cavity, and under certain conditions it can get into the blood and will colonize the heart valve. Once it vegetates on the heart valve, it then becomes very difficult to eradicate it — because, again, it’s a biofilm — and very difficult to eliminate.

    Question: Tell us a little bit more about your research. It’s sounding like there are really there are two distinct systems here we’re talking about in terms of phages, or not?

    Answer: Phage is one system and phage enzymes is a whole different system. They’re both unique. Phage, we eat, drink phage all the time. As I’ve mentioned, every gram, every gram of soil has about…a hundred million phage in it. Every cc of water has about…the same number of phage, so we are inundated by phage all the time, and we eat, drink phage constantly. So, if you use phage for a therapeutic, I don’t think it would cause any detrimental effects in individuals. The real question comes in: will the FDA approve a cocktail of viruses or phage that will not be exactly the same from lot to lot?