Tagged: antibiotic resistance, antimicrobial peptides, ca-mrsa, dental biofilm, dr. michael otto, medical biofilm, mrsa, mrsa biofilm, phenol-soluble modulins, psms, quorum sensing, s. aureu, s. epidermidis, staphylococcal exopolymers, usa 100
February 25, 2010 at 4:09 am #2811
The video interview is complete, the 11 minute distillation is now available. See an excerpt from the video interview in the next post.
Chief, Pathogen Molecular Genetics Section – Senior Investigator
M.Sc., 1993, University of Tuebingen, Germany (Biochemistry)
Ph.D., 1998, University of Tuebingen, Germany (Microbiology)
Editorial Board Member PLoS ONE, Recent Patents on Anti-Infective Drug Discovery
Description of Research Program
The Gram-positive bacteria Staphylococcus epidermidis and Staphylococcus aureus are the most common pathogens in hospital-acquired infections. The costs related to infections caused by these strains in the hospital setting are enormous and represent a major health care burden. Furthermore, the more recent combination of extraordinary virulence and multiple antibiotic resistance in community-acquired methicillin-resistant strains of S. aureus (CA-MRSA) poses an additional severe threat to public health.
S. aureus may cause a multitude of serious infections, including toxic shock and scalded skin syndromes, endocarditis, and pneumonia, to name but a few. In contrast, infections with S. epidermidis are usually chronic and less severe. The most important type of disease caused by S. epidermidis is the colonization and infection of indwelling medical devices.
The outcome of infections with S. epidermidis and S. aureus is closely linked to their interaction with human host defenses. Thus, mechanisms of immune evasion such as the formation of biofilms represent significant virulence determinants in chronic infections with staphylococci. The long-term objective of our research is to provide the scientific basis for the development of drugs interfering with these mechanisms. To that end, we are investigating the molecular biology, biochemistry, and epidemiology of the interaction of staphylococci with host defenses.
Major Areas of Research
Phenol-soluble modulins (PSM): a novel class of staphylococcal virulence determinants
PSMs are a family of alpha-helical, amphipathic peptides that are secreted by many staphylococcal species. We discovered that S. aureus and particularly CA-MRSA produce strongly cytolytic PSMs that lyse human neutrophils and have a key role in virulence. Furthermore, the PSM-mec peptide represents the first known example of a staphylococcal toxin gene that is transferred together with antibiotic resistance. PSMs may represent promising targets for anti-staphylococcal drug and vaccine development.
Evolution of virulence in CA-MRSA
We are investigating the molecular determinants responsible for the exceptional success of CA-MRSA in causing severe disease and spreading sustainably in the human population. In particular, our laboratory explores differential expression of core genome-encoded virulence determinants as a basis for CA-MRSA virulence.
Gene regulatory processes during pathogen-host interaction
Our work has provided important insight into the role of the agr and luxS quorum-sensing systems during biofilm formation and inflammation. Furthermore, our findings on agr control of psm genes have allowed a glimpse on how quorum-sensing dependent regulation of virulence in S. aureus has evolved.
Antimicrobial peptides are a key part of innate host defense to bacterial infections. We have identified the first antimicrobial peptide-sensing system in Gram-positive bacteria and investigated its role in S. epidermidis and CA-MRSA. Further work is focused on the interaction of staphylococci with the anionic human antimicrobial peptide dermcidin.
Physiology of staphylococcal biofilms and biofilm-associated infection
The formation of sticky, multicellular bacterial agglomerations called biofilms dramatically complicates the treatment of staphylococcal infections. Using genome-wide transcriptional profiling, we have shown that gene-regulated processes in an S. epidermidis biofilm lead to a non-aggressive and protected form of bacterial growth with low metabolic activity, optimally suited to guarantee long-term survival during chronic infection and resistance to antibiotics. Furthermore, we have developed real-time monitoring of S. epidermidis infection using bioluminescent imaging. We are currently focusing on the mechanism of biofilm detachment and its role in biofilm-associated infection.
Role of staphylococcal exopolymers in immune evasion
Polysaccharide intercellular adhesin (PIA). We have shown that the exopolysaccharide PIA contributes to S. epidermidis resistance to innate host defense. Furthermore, we identified enzymatic modification of PIA by the IcaB enzyme as a crucial factor determining the biological function of PIA in biofilm formation, colonization, and immune evasion.
Poly-gamma-glutamic acid (PGA). Our research has shown that S. epidermidis PGA is crucial for survival in the human host during commensal life on the skin and infection. PGA might be a promising antigen for vaccine development against S. epidermidis infection.
March 24, 2010 at 2:19 am #3363
Question: What can you tell us about these kinds of microbes that are affecting pre- or post-operative patients? Is it just a device-based kind of situation, or are there other situations where the patients could be infected in some way?
Answer: Well, we have to leave the Staph epidermidis field here. We are talking now mostly about Staphylococcus aureus, where clearly, the device-associated infections are only part of the infections that the organism can cause. So something that has been, all over the media over the last two or three years are these so-called community-associated infections, where we leave the setting of the hospital completely. So the new thing here is, we always had infections that occurred in the community, but these were usually not caused by strains that were methicillin-resistant. So, so the big thing is here that MRSA, infamous MRSA, is not limited to hospitals anymore, but can infect healthy patients in a community setting.
So, what we were mostly interested in as pathogenesis researchers, more recently, was what makes the strains more virulent? What makes them so aggressive that they can attack healthy people: football players, gymnasts and high school students? We think that increased expression, for example, of these phenol-soluble modulins that we that we talked about, but also increased expression of other toxins, contributes to the increased virulence potential of these strains.
Question: Research on polymicrobial biofilms, perhaps made of fungal and bacterial species, suggest that different microbes cooperate to build a tougher biofilm. One particular new study that Im sure youve seen states that Candida albicans is a foundation for interstitial, interstitial Staph A. And, in fact, that same study confirms that, that biofilm can lead to antibiotic resistance, in that case, vancomycin. Can you comment on the link between polymicrobial biofilms and antibiotic resistance?
Answer: So we have to, distinguish; I think, between different types of infection when we talk about the importance of polymicrobial biofilms. What we usually study does not really tend to be polymicrobial biofilm. So, staphylococcal infections on medical devices are usually just due to one species or one strain
So thats one thing. But then also in, in medical biofilms, there are medical biofilms that tend to be polymicrobial, for example the typical dental plaques. These are super-polymicrobial, there are hundreds of species involved there and you can imagine how difficult that is to be investigated in a laboratory. We have no clue yet on how they really interact, how maybe species that were not even able to culture, might influence the physiology of such a polymicrobial biofilm, and then, as you mentioned, what that means for antibiotic resistance, for example, also for horizontal gene transfer that one bacteria might spread, antimicrobial resistance that it has acquired to from the others in the polymicrobial biofilm I think we know that this is going on, but we are far from understanding how much that matters..probably it will matter a lot.
Question: The concept of quorum sensing is now roughly more than four decades old, so, what have we learned? What have you learned since then about quorum sensing and the weird world of bacterial communications?
Answer: Quorum sensing is one of the most interesting bacterial phenomena that have been investigated, and, almost ever since it was discovered, people have suggested quorum sensing might be something that might be exploited, to come up with antimicrobial drugs.
So the idea here is that quorum sensing is this phenomenon by which bacteria sense the presence of other bacteria. So when there are many bacteria present, then a signal becomes so concentrated that all bacteria in the community sense the signal and upregulate many genes, and, very often, these genes comprise virulence factors, toxins, sometimes also biofilm factors. And then people thought, Um, well, instead of targeting with a drug all these different toxins, why dont we just target the quorum sensing system. Then we can downregulate; we can abolish the expression of all these bad things…”
Now, in principle, that sounds great seemed to make sense. For example, Pseudomonas aeruginosa, biofilm formation seems to be a main virulence factor in this bacterium, and also very closely related to quorum sensing. But we also understand now that, for example, in the bacteria that we are investigating, this might not always be connected the way we want. So when we block quorum sensing in staphylococcus, things happen to the biofilm that we dont really want the biofilm actually grows thicker.
And so, so, these things seem to be differentially regulated in the, in different bacteria, so I think there was a little bit too much of the euphoria in the beginning about these quorum sensing blockers, and we now have to look at every bug in particular…
Question: Lets talk a little bit about transmission. If you look at the hospital environment, where is MRSA and all their little friends found in the hospital? What are the top offenders as far as youre concerned, and in terms of the pathways of transmission?
Answer: Well, that goes for the hospitals and that all goes also for the interactions in the community. The dirtier, the worse. So something that helps against the transmission of MRSA in whatever environment is cleanliness. And there are clear correlations between hospitals that tend to be cleaner or that have policies in place such as, in the Netherlands, for example. There are clear Search and Destroy policies, when MRSA is found somewhere. Then this is followed up by going back to the family origin where it came from (the original contamination point) and is something thats not practiced in the United States and as a consequence, MRSA infections here tend to be at a very high frequency.
So cleanliness is definitely very important. For community-associated infections, its very easy to just use soap and water which will get rid of the MRSA on hands and so forth. Maybe I can add a little bit on that Search and Destroy thing because, there, theres a big discussion going on: why, why isnt that initiated in the United States? So, people from the Netherlands and other Scandinavian countries mostly have very low MRSA infection rates. They, of course, would suggest, to do this same thing here, but then there are other people, from the clinical field, and I have to admit that its not so much my expertise, but, I hear from my friends from the clinics tell me, . Theirs is just a little bit pessimistic view, but it might be true.
Question: What progress is being made to eliminate biofilm growth on devices and prosthetics or within the patient once theres MRSA with biofilm infection?
Answer: What usually happens is that one tries antibiotics and in most cases, one has to accept that the antibiotics dont work. Even for multi-drug resistant strains, theres always still now vancomycin. Well, once in a while, that might not work, and then the only thing that works is taking the catheter out and putting a new one in. And if thats more than a catheter, if its prosthesis to replace, thats of course not very nice for the patient, though its cost-effective
Researchers are trying to find new therapeutics to combat these infections. There are two main ways: there are material researchers who try to improve the material of the catheter, meaning that they change the surface so bacteria are becoming less attracted — they stick less to the material surface.
There are molecule biologists, immunologists and we are trying to understand by which means the bacteria cause biofilm, so that we would be able to directly target them with novel therapeutics; the genes and proteins that are, or other molecules that are involved in, in biofilm formation. Quite unfortunately, I have to say, none of these two approaches has really worked out that well so far. On the material side, there has been improvement, of course, but what happens in the human body is that whatever materials you stick in, the human body covers it relatively soon with matrix proteins. And the bacteria are very good at attaching to these matrix proteins, so that, in the end, what is the material surface doesnt really matter that much.
No matter what these people have come up with, the bacteria are still able to form a biofilm. And the same is also true for the other side. There hasnt been so much success because biofilm formation by most bacteria tends to be multifactorial and its very difficult to come up with a therapeutic that targets all these many things. This is why people were so euphoric about the quorum sensing blockers, which might not have turned out that well in the end. So, there, again, were trying a lot, but the, the redundancy of these biofilm factors causes us a lot of trouble.
Question: Some of your research involves what you call phenol-soluble modulins. It shows that the staph peptides can actually lyse human neutrophils, or even cut red blood cells in half. How does that work?
Answer: This is a relatively recent development. These are peptides that we just discovered and published two years ago. These are a new class of staphylococcal toxins, and what they do, as you said correctly, is they poke holes in neutrophils; neutrophilic cells are the main defenders of the human body against the bacterial infection.
June 15, 2010 at 6:02 pm #2812
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