The Future of Anti-Microbials For SIBO – A Discussion With Dr. Bryan Davies

Dr. Bryan Davies is one of the leading researchers in the field of antimicrobial discovery and development. We had an insightful discussion with him on the future of anti-microbials for SIBO. Here are the highlights:

  • Cancer treatment has moved on from small molecules to biologics and cell-based treatments. Why is SIBO treatment still stuck in the world of small molecules discovered decades ago with a simplified theory of killing bad microbes and promoting good microbes?
  • Differences between conventional antibiotics and antimicrobial peptides. Why is there so much excitement for antimicrobial peptides?
  • Antimicrobial peptides work by targeting the bacterial membrane, so it is relatively harder for bacteria to develop resistance.
  • Colistin – an antibiotic from 1960’s targets the bacterial membrane just like the antimicrobial peptides. It is non-absorbable and shows low toxicity in the gut. Should it be considered as a second line of treatment for SIBO?
  • Lot of antibiotics – Rifaximin / Ciprofloxacin work great in the petri dish but not in the human body. We need better in-vitro assays and animal models for SIBO.
  • The future of Gut therapeutics maybe delivering highly targeted antimicrobial compounds via engineered good bacteria. This way the bacteria can get to the specific location in the intestines, pierce through the gut mucosa and biofilms, and target the specific pathogens without harming the beneficial bacteria.

TRANSCRIPT

Sumit Khetarpal: Hello Everybody! I’m Sumit Khetarpal on behalf of the gut warriors where one of our goals is to enable drug development for IBS and in that regard, we have a very special guest today – Bryan Davies. He’s an expert in antimicrobial research discovery as well as development. He has a PhD in microbiology from MIT, post doc from Harvard Medical School and he’s now a professor at UT Austin where he’s leading his research in antimicrobial discovery and development so Bryan, let’s take a few minutes – please tell us more about yourself what motivates you about antimicrobial research and broadly speaking what your research group does.

Bryan Davies: Thanks for the opportunity Sumit! What would be the best place to start? My interest in microbes I think developed when I recognized just how many things around the world both healthcare for agriculture for environmental recycling that microbes had a hand in we’re certainly aware of them from the standpoint of infection we certainly hear about antibiotic resistance from clinical complications from infection but there’s also entire areas within agriculture that they are both important for improving agriculture as well as detrimental for agriculture they’re they just seem to have so many uses and importance in our world but I was really just captivated by that breadth of potential in them um and then that coupled with the sense that uh you could manipulate them in so many ways it was just incredibly intriguing I grew up working in a hardware store and there was always a side of me that just enjoyed building and constructing and when I think of a problem that we observe out in the world we have to know about the problem we have to understand all the parameters around it but then we need to be able to do something about it we need to build something we need to fix it in some capacity and microbes just really had that had all sides of the equations for me so much to learn so much importance and yet a great ability to build and to engineer with them to go to look to tackle these problems that were that many of the problems that we’re looking to face in the world. My group at UT Austin is focused on microbes from the standpoint of control we want to be able to control microbes both the detrimental ones that cause infection but also the positive ones that can do good things for us we really view these as uh complementary or synergistic uh and by understanding one you can understand the other uh much better so for example um when it comes to uh infective bacteria something like e coli which I think many people will have heard the name of there’s certainly deadly e coli strains that can cause severe disease but at the same time there are these probiotic strains of e coli that if you ingest them they can actually help with some gut related conditions so really appreciating what the differences are in those microbes gives a to us a keen insight into what makes something a pathogen versus a potential therapeutic in addition to understanding the microbe we also want to build new modalities for their for their treatment and control when we think about controlling a microbe it’s uh it’s because we’re doing something to it we’re exposing it to a something and uh what most of us I think would be feel comfortable with are antibiotics names like penicillin or tetracycline are probably common to many folks and these are small molecules that we’ve had for many decades and the small molecules will always have an important part in antibiotic research and treatment of bacteria whether it be for pathogens or controlling communities but what kind of caught our attention was when we started to look at other fields that if you look at this say the fields of cancer specifically they as well started with small molecules for initial cancer treatment but since then they’ve moved into you know the field of biologics antibodies peptides small proteins and it’s not that these are necessarily better or worse than small molecules it’s just that they can do different things so then they expand their ability of how they can treat cancer this more recently has moved into cell-based treatments for cancer where we can actually uh take human immune cells alter them put them back into the body and start treating cancer and it just really started to make us scratch our heads well why are we still largely in the world of small molecules from 60 years ago with bacteria when there’s been all these amazing technological advances so what we focus on as far as the molecules we use to control bacteria we focus at the moment on biologics these are antibodies peptides proteins and asking how can we start to think about these and use them in ways that give us an extended ability to control bacteria that small molecules just have not been able to by joining these two areas of the lab by understanding microbes their pathogenic ability as well as their probiotic and positive abilities and fusing this with our understanding and opportunities to make and deliver these new classes of proteins and biological control agents we’re hoping to open new areas uh in microbial control in general where we’re looking where we have uh cell based as well as protein-based ways of controlling microbes as well as their communities but also possibly giving microbes ways to influence the host in beneficial ways as well. So, that’s largely what we do.

Sumit Khetarpal: Excellent – that was that was a great summary so one of the things you talked about as far as part of technological advances was the peptides and it looks like the field is almost taking a turn where um and I wanted to understand these peptides the antimicrobial peptides how are they different from conventional antibiotics and why is there so much excitement around the antimicrobial peptides in the research community

Bryan Davies: I’d say the large differences as we think of the chemical structures of small molecules versus peptides are a series of strings of amino acids the same things that make up all of our proteins in our body and I’d say that historically the antimicrobial peptides that have been researched by the majority of the field to date have actually come from the innate immune systems either from our cells or from other organisms so antimicrobial peptides have been used for as long as there have been organisms as a as an innate immune response these are linear change chains of amino acids that are released by a cell and they can go and they can kill a bacteria that may be trying to cause harm. The small molecule space is off is also largely dominated by natural compounds um these tend to be good way of phrasing it they tend to be they’re largely produced by bacteria they largely come from bacteria that are that were that were derived in the soil and they’re used in kind of microbial competition their structures if you were to look at them on paper they have a variety of cyclized versions they have fatty tails added to them there’s not I think a clean way to broadly say what all small molecules look like because there is quite a diversity I think perhaps the easier way of looking at it is saying why are peptides different and the large difference there is that these are linear strings of amino acids that are by and large found in natural immune systems that folks are trying to take advantage of both for their antibacterial properties but as but also for their potential in manipulating the host immune system I’ll work on a better and cleaner definition between peptide and small molecule so uh to your second question about why is there excitement around them um I think it comes from really kind of two directions the first direction is that they do represent this new area of chemical space small molecules have been amazing they were the first antibiotics studied they did well for a long period of time but it seems like it’s just becoming harder and harder to find new small molecule antibiotics um not necessarily for a lack of trying uh but I believe the number and these can be I’m gonna make some rough numbers here but I believe the last new truly new antibiotic was discovered in and around the 1960s or 1970s depending on how you do the math and despite a lot of effort there’s been challenging challenges in finding new ones the thought may be that perhaps we’ve somewhat exhausted the natural resource at least these at least the areas that we’re looking at for small molecules um peptides on the other hand they’re quite by comparison they’re quite easy to synthesize you’re just making this linear string of amino acids and they can have all sorts of structures and diverse chemistry to them and we’ve reached a point where we’re now able to chemically synthesize them with relative ease we’re coming up with new platforms that are able to screen for their activities more effectively and this is allowing us I think to take to take a real step at asking what is the breadth of antimicrobial peptide chemistry out there that we can take advantage of and now we have the tools to really go and explore it I think then the excitement comes from that feeling that we may be at a point now where the technology has advanced that we can take advantage of these uh of peptides in ways that we couldn’t 10 or 20 years ago.

Sumit Khetarpal: Got it got it now looking at the field from outside there is clearly a antimicrobial resistance problem with conventional antibiotics you know very fast these microbes develop resistance even to the latest drugs and from what I read the antimicrobial peptides they do not have as much of a resistance problem is that fair or would we still see you know a new antimicrobial peptide and next thing you know the smart bacteria have figured out how to get around the antimicrobial peptides.

Bryan Davies: So my bias is that any time we try to try we begin to treat a bacteria it will find resistance where I think the difference comes is the positive sides of antimicrobial peptides the aspects that are championed for low resistance is that they by and large tend to target the bacterial membrane the cell membrane that surrounds the bacteria they’ll bind this membrane they’ll poke holes in it and the bacteria dies because they’re binding the membrane the ability it’s tricky for a bacteria by itself to just all of a sudden change what its cell surface looks like um I’ll make a comparison um there is a uh classic antibiotics will often go after a specific protein target they bind the target and they inhibit it so the bacteria can often make a single amino acid mutation in that protein target and that antibiotic is now no longer effective the argument is that it’s not nearly as easy for a bacteria to make small changes in its cell envelope cell membrane that would then all of a sudden make it resistant to peptides and we can actually see this in the lab if you take an antibiotic like penicillin and you expose a bacteria to it repeatedly you can watch again gain resistance in a fairly short period of time if you expose a peptide to a bacteria they often remain sensitive for weeks if not months I believe typically I see lab experiments go to as far as a month so from that perspective peptides are less likely to gain resistance so here’s my big but though um there is a uh well-known antibiotic that is now again being used clinically I believe it was discovered in about the 1960s called colistin and like antimicrobial peptides it also targets the cell membrane the thought was also in the lab we typically don’t see a lot of colistin resistance and because it’s targeting the membrane it’s unlikely that we’re going to gain um resistance broadly across the globe then in about 2000 shoot I’m gonna be off on a date but 2010 plus or minus five years because I’m probably off on a date um what was observed is that some bacteria didn’t go ahead and on their own just change what their surface looked like they instead acquired a gene from the environment and which there’s still debates on where that gene came from but they acquired this gene from the environment that then on its own could decorate the outer membrane imagine you know like putting i don’t know uh you know lights up on your house they this gene was able to decorate the outside of the bacteria that all of a sudden colistin was no longer no longer working anymore so my view is that in the lab antimicrobial peptides look like they have a great ability to not promote resistance but if we start using any peptide broadly out there in the in the environment in the clinic you name it I am positive bacteria will find a way around it they’re just smart right and there’s a lot more of them than there are of us.

Sumit Khetarpal: fascinating – yeah it makes our job harder and keeps us at our toes that’s for sure

Bryan Davies: it does

Sumit Khetarpal: great uh so you know this this field around antimicrobial peptides I’ve seen research literally explode in the last 20 years or so but still we see very few antimicrobial peptides in the clinical trials so um help me understand what’s going on why are there so few peptides making through the translational stages

Bryan Davies: there are three significant problems with peptides I break them down to see three simple categories um the first category is and this was observed with many um of the first antimicrobial peptides observed is that they act by lysing a bacteria’s membrane but they weren’t very specific which means if you also expose them to say red blood cells or human cells they would similarly damage those human cells so when you’re thinking about an antimicrobial peptide that targets a bacterial membrane you have to make it specific so there’s this interesting um I still think it’s interesting because I don’t think it’s entirely understood of how do you make an antimicrobial peptide that it’s its mechanism of action is to break membranes but it can selectively do it against a gram against a bacteria but not against the mammalian cell so we’re making progress there and there be there are more and more examples of um peptides with this selectivity so I think we are that was a problem and I think we are getting around it I’m going to kind of go through these three problems and increasing level of difficulty the second problem with peptides is when we think about using them for treatment it’s really important to understand where are we looking to treat treating a condition in the gut is very different than treating say a bloodstream infection and most peptides have been thought of as antibacterial work for infections like bloodstream infections like lung infections and so on your body though among other things makes a lot of proteases enzymes that degrade proteins and antimicrobial peptides in their natural state are really just short proteins um and uh the an issue is that when we inject these into the body that the proteases that you have in your body naturally degrade them so they tend to be very unstable so for example if you were to inject a typical peptide not even an antimicrobial peptide but just any kind of peptide into your bloodstream it would not be uncommon for it to be completely eliminated from your body in less than 10 minutes so you can imagine that if you have an infection or you’re trying to treat a microbe that if you give somebody a an injection and it’s gone inside of 10 minutes well that’s not really going to be able to treat the infection very well so what we’ve had to do and where we’re again making better and better progress is modify is having a peptide that can kill a bacteria that’s your starting point you show that it can be selected against that bacteria check that box and then you need to start manipulating it you need to start changing its chemistry you need to start changing how the amino acids connect together and we are at a stage now where we can produce peptides that are completely resistant to degradation in the body so those are your first two big checks and we’ve got those so we can get peptides that are selected for bacteria and we get peptides that are very stable in the body the last one is still an ongoing challenge when you think about bloodstream infections this is very different than the gut and I’ll look forward to getting into that but when you inject a peptide or any molecule into your bloodstream um our body does what it does and has evolved to do really well which is that it clears stuff out of the body and any molecule that is um so the number the rough number is 60 kilodaltons and that’s just a way of saying that um I’m trying to think of a good reference for a kill though to put it into a another kind of metric uh measurement but a kilobyte is just a measure of weight it’s like using grams or kilograms and any protein that is under about 50 kilodaltons is very quickly cleared out of the bloodstream most peptides are about 0.5 or less kilovolts wow so they’re going to be cleared very rapidly from the bloodstream once they do they tend to accumulate by and large peptides anyways by and large in your kidneys as they accumulate in your kidneys they through mechanisms which we do not understand at the moment they can start to cause damage to your kidneys a condition specifically termed nephrotoxicity where they end up causing uh your kidney to no longer function properly so we recently saw this with a peptide antibiotic called um I never say this one correctly muvapavadin mira paladin. google some phrase like that.

Sumit Khetarpal: Yeah I remember reading about that.

Bryan Davies: right and so it did wonderful animal studies it had all these qualities very stable selective for bacteria and it was actually a little bit different in that it didn’t actually target the membrane it even targeted a specific protein but what they ended up finding was that in phase three especially with patients who were already had other kind of issues with them is that they again started to see this kidney toxicity building up again this is not a problem just for peptides it’s a problem actually in antibiotics saying in general isn’t fair but there’s many antibiotics that we that we’ve been using for years the one colistin that I mentioned also causes kidney damage there’s other ones out there that people may have heard of vancomycin is a big one it’s used to treat uh drug resistant staph aureus this also builds up and causes kidney damage I can’t give you an exact reason why but one issue could be is that if you were to compare the treat the doses that we have to give people for antibiotics versus the treatment of other conditions say like diabetes if you take an insulin injection you actually receive very small amounts of insulin it does its job it’s cleared and it’s done with infection when we’re thinking about treating UTIs or lung infections the dosing is actually quite high and you’re doing it for quite a long period of time and as these get filtered out of the blood they just accumulate so we see this issue with several types of antibiotics we also see it in the cancer field when they have to give kind of long-term drug treatments um so where I see some real innovations coming in that way in my regard is that there are there’s a couple clinical trials maybe a couple’s not right i think just one but there’s folks who are developing compounds some of which already exist where they actually block the uptake of drugs into kidneys so they tend to be excreted faster if that can actually be harnessed I think that’s really going to open up the field because we can make peptides that are selected for bacteria we can make them that they’re stable and if we can just get it so they don’t accumulate in the kidney I think that’s going to be the trifecta that really opens up this field for controlling a broad range of bacterial infections and I realize my answers tend to go on for 10 minutes so I can shorten them

Sumit Khetarpal: that’s okay you’re doing great um so you know I have seen so far the focus of research and rightly so really on life-threatening infections from ESKAPE pathogens and I fully understand it deserves the urgency because they’re life-threatening infections at the same time pretty much similar bacteria you know your Klebsiella, your E-coli, your Citrobacter, Enterobacter they are implicated in chronic diseases like small intestinal bacterial overgrowth so there with SIBO to be short form and that’s where our community is interested in innovating so with SIBO you have bacteria like klebsiella which if it’s in the smaller numbers it’s perfectly okay in the intestines but what happens is that for a variety of reasons klebsiella explodes and then it causes a host of different issues so you talked about a lot of challenges with the antimicrobial peptides when it comes to injecting via the bloodstream which is okay which I think which makes sense for the life-threatening infections but for SIBO one of our requirements is that it needs to be non-absorbable and it needs to go through the gut so far I have not seen I did a literature review and I did not see people working on a problem where they are delivering antimicrobial peptides through the gut can you talk about some of the challenges of developing antimicrobial peptides for gastrointestinal tract

Bryan Davies: I think the GI offers a real opportunity because all those issues that I was describing as far as um toxicity within the kidneys as you rightly mentioned uh with the with in regards to absorption this is no longer a problem in the gut peptides by and large when you take them orally are not absorbed through the gut this is sometimes viewed as a criticism because then folks say we always have to do injections for treating other types of infection but if your goal is the gut then I think there is a real opportunity there because the when you take them orally they’re immediately going to be able to um I’m going to say get in the region I’ll talk about the exact area in a second but they are going to be able to at least enter the gut once swallowed and you don’t have to worry about building the kidney and I think a lot of other toxicity is going to be mitigated I think that so I think there’s a real opportunity the big one with the GI tract I would say again is the stability uh you know the PH of your gut is you know in and around one or two there’s again a lot of proteases and your stomach in in a sense is made to degrade protein so that as we eat food you know you can get this so the idea of making these peptides stable would be just as critical there but again I think we can get there with it um I the closest thing that I have seen that suggests that there is an opportunity is that I need to go back and double check this in fact I am though nearly positive the antibiotic I was speaking of before colistin um it has only been reintroduced into the clinic because there’s problems with drug resistance in general it was not used for many years because of toxicity problems but where it was used was actually in the farming industry and they did find that when you have animals take these take colistin orally it was active in the intestinal tract so that to me is just an example and oh I’m sorry I should back up colistin while not truly an antimicrobial peptide is protein based it’s a small cyclic peptide there’s some other modifications to it but it is a small cyclic peptide so I think that that is a little bit of tantalizing information that the right peptide can be active in the gut so I think there’s certainly opportunities there and I think that if your peptide is active against e coli or klebsiella for a bloodstream infection and yes why not go after my gut it makes total sense I think a challenge that I’ve seen but I also just think it’s because the community has not been sufficiently engaged then again I’m saying this is somebody who hasn’t really tried themselves it’s quite easy for you to make an animal model of a bloodstream infection I think a representative animal model for SIBO or IBS still remains challenging so part of the part of the problem could be that we don’t have sufficient animal models to accurately represent what SIBO would be like so it may so we we’d have to put some more thought into what would be the appropriate model as I’m saying that I’m kind of thinking out loud but there may be some other substitutes we could use um I think there’d be ways of making models anyways I think out loud so excuse me um I’ll if I diverge too much um there’s an opportunity for peptides I think the animal models are not as advanced as they could be and I think that’s something that we could certainly lean on the other aspect I do see is that the gut is to say extremely complicated is putting it lightly the small intestine alone is six meters typically an adult and one thing that I think we still don’t understand we still need more research on is where are the bacteria present um it’s unlikely that they’re just distributed throughout the intestine they’re probably collecting in certain areas that they’ve been able to establish themselves in and make a home in. Another big aspect is where they are in relation to the mucosal layer at least in my opinion it is because you’ve got the um intestinal wall where the human cells are but then you have this mucous layer which in a healthy adult is often a hundred times the size of a bacterium and you’ll often have this mucus layer and the bacteria in a healthy gut kind of sitting on top of it doing their thing oftentimes in disease and I’m extrapolating from other diseases like when e coli infects the gut or when salmonella infects the gut that they’re often able to burrow into this mucous layer and that mucous layer can actually act as a barrier to many compounds so I think what we need I think this is actually all addressable but what we need is a good animal model that we can start to pull apart whether or not our peptides can work in vivo and even before that we need to come up with some better in vitro conditions what I mean by that is if I’m going to make a peptide that I think can be active in the bloodstream I’ll test it against bacteria in a test tube in their normal growth medium that’s fine but then I’ll also do it I’ll do that same assay but I’ll grow the bacteria in human serum to try to replicate the bloodstream similarly I bet we could come up with similar in vitro assays in fact I’m sure they exist if I look if we look in the literature there’s probably in vitro conditions that better represent what that gut environment is like which will let us know which peptides can access the bacteria in that state versus which ones may be blocked by mucus in the gut bile in the gut PH changes in the gut these sorts of things. I don’t know that I entirely answered your question, but I think I outlined at least a few barriers that can be addressed and should be addressed as we look at peptides for gut treatment

Sumit Khetarpal: great no I think you talked about something I was going to ask you um which is the bacteria entrance in biofilms not sure if mucus and biofilms are um separate entities but let’s just say um some sort of combination of biofilms and mucus um so when you go through the blood route versus you go through the gut route is there an inherent advantage going through the blood route because you know some bacteria like klebsiella or e coli that’s biofilm forming it’s going to form the biofilm anyways so if you go through the blood route how is it better or different than let’s say going through the gut route for attacking bacteria entrenched in mucus or biofilms

Bryan Davies: I think they’re I think it’s a similar problem and I think you talking about biofilms is really important because you’re I think that you’re correct whether we’re talking about the gut or whether we’re talking about a bloodstream or a lung infection like cystic fibrosis is another you know well-known disease where there’s a lot of mucus there’s a lot of biofilm I’ll mention something on that in a second anytime you have these sugars that the bacteria these really thick gloopy sugars that the bacteria are able to hide themselves in it becomes a problem and a lot of antibiotics their activity is either greatly decreased or it’s just completely absent so identifying compounds that can break up biofilm or that are able to act on it regardless the bacteria regardless I think are critical and I have seen peptides that can do this there are several peptides out there that I have seen that you can grow bacteria they can form a biofilm and the peptide can actually penetrate that biofilm break it up and kill the bacteria so that is possible it’s not all peptides but there are certainly examples of peptides out there that can do it biofilm and there this is this is getting a bit into the weeds but I think it is important to consider that your gut with or without bacteria is going to make mucus and that in a bacteria can bury themselves kind of in our natural mucus that’s kind of a protective layer on top of that they can make their own biofilm as it’s called which is just a whole mix of sugars and protein and DNA that they kind of shoot out of themselves an additional layer on top of that to make it even more complicated is bacteria especially like klebsiella produce an initial of additional sugar called capsule and they can make so much of this that if you grow these very encapsulated bacteria on a plate and you go to scoop them up with a stick it looks like you’re scraping gum off a plate there’s just this big line of sugar that comes with them . These are all issues because you know it’s not hard to imagine you know if you um if you’re a microbe and you’re trying to hit it with an antibiotic and it’s exposed well then it’s exposed but as you put on more and more in different layers of its typically sugars just these long stretches polymers of sugars as you make more of this goo and gloop around them it’s harder and harder for any drug we try to make to get through that through it so I think this can be in my view part of this initial screening stage where you would take say you know half a dozen represent representative bacteria from SIBO identify peptides that can be selective that aren’t going to be degradable and kill them and then you also have to start building on which ones of these peptides can get through a biofilm which ones of these peptides are inhibited or not if I add simulated gastrointestinal fluid I know you can purchase i know that’s available for purchase which ones of these are also activated acted against bacteria that make these big capsules all of these assays are manageable I think they’re all doable and they just in my view they have to be incorporated into your decision tree to say here’s my initial pool of some number of peptides how do I then filter down so that by the time I go into an animal model I have my best shot that you know this is the one that’s likely going to be able to give me all the properties I’m looking for to kill my bacteria in the gut it’s possible it’s not hard but you know things worth doing aren’t easy so I think it’s just a matter of doing the work

Sumit Khetarpal: Absolutely. So, let’s talk about pep w you know I read your research paper excellent work by the way. What challenges you have already solved and what remains with pep w um so talk a little bit about future direction of pepW.

Bryan Davies: So pepW was a peptide that we made that we were able to we were specifically interested in klebsiella I apologize I don’t know why that picked up um we were interested in killing the bacteria klebsiella and klebsiella as I mentioned makes this very thick polysaccharide coat. We had a we found a peptide that was able to kill many bacteria but it couldn’t kill klebsiella so we evolved this peptide towards a form that could and it was called pep w and what we observed is that it had a unique ability to bind to klebsiella’s capsule and aggregate it in some way that exposed the bacteria to more peptide that could then kill it so what we’ve been focusing on with pep w is this idea of being able to disrupt klebsiella’s capsule which as we were just describing is a is a real impediment to being able to kill the bacteria so the postdoc um uh Dr. Renee Fleeman who did all that uh who was the first author and did that work she’s been focusing on understanding via can we make more peptides do natural peptides even exist where we can take advantage of this ability to remove klebsiella’s capsule and then gain access to the bacteria this has actually inspired a few additional peptides pep w was a great um proof of concept the challenge with pep w going forward in our opinion is we believe that there will still be from a clinical perspective there for with long-term use we think there may be still some toxicity and certainly irritation within the gut as far as its interaction with epithelial cells so we’ve been looking now to try to step up the next question which is can we make peptides which are even more stable than pep w that still have all this ability to aggregate capsule but that are really going to be toned down as far as any sort of interaction you have with a host cell academically we’re very much interested in understanding the ability of peptides to aggregate capsule and to get through biofilm because as it stands right now there are many ex there are examples of peptides that can do both if we do searches for biofilm disrupting peptides we can find them but when you tend to put two peptides side by side one that disrupts a biofilm and one that does not or one that disrupts capsule and one that does not it’s very hard to just look at the sequences and know why it’s very hard to know what those differences are it’s still very um uh empiric as far as test and see whether one works and one doesn’t so we’re also developing we’re trying to we’re developing some ai methods whereby our first goal is just to see can we start to predict a peptide’s ability based on its sequence can we predict the fold of the peptide based on its sequence and then how can we extrapolate that to the potential to get through capsule and to get through biofilm so pepW is a great starting point and we continue to work on this idea of peptides either around pep w structure or inspired by it that can aggregate capsule but then how do we learn from that and start to begin start to develop predictive abilities for making stable peptides that don’t affect human cells that also have these properties so that first of all we can make better peptides but also coming back to an earlier question you asked it could be great if we make a pepW and it works but then what happens six months later or a year later if we have resistance we want to have a pathway where we can have a pipeline of these ready to go each one being able to remain active when the one before it becomes inactive due to some resistance mechanism

Sumit Khetarpal: got it excellent. All right I think you’ve covered a lot of ground here so let’s talk about um. well you know it’s always challenging in a research field you are you’re looking for more work requires more funding which is not necessarily easy to come by so let’s say you had infinite resources how would you tackle this SIBO problem um especially as it relates to bacterial pathogens and the biofilms and everything so I think everything that you know if you can if you can and you don’t even have to limit yourself to peptides necessarily I would say you know you’re an expert in the field you know a lot about these things. Let’s just take a bigger view and say you can do anything you want you can use any technology how would you attack the SIBO problem.

Bryan Davies: um it’s something that we are looking at right now we’re not doing it specifically for SIBO but we’re doing it for broadly influencing conditions within the gut um I think I think one of the first things we need to do with SIBO though is I don’t I think that it’s again an umbrella phrase for probably many underlying conditions um the work that I’ve seen out there are certainly bacteria like e coli and like klebsiella that are commonly found in in patients who suffer from this but it would not surprise me if you took you know 100 people all suffering from it if the actual microbes in their gut were a little bit different that wouldn’t surprise me one thing that is nice is that as diagnostics become less expensive as sequencing becomes better I view this condition as well as many other conditions as benefiting greatly from improved diagnostics so if you know if somebody is rushed into an er and they’re suffering from you know an infection that they’re going to die immediately then there’s not really much of an opportunity to look for a treatment you just have to give them something that you hope is working but I feel like with conditions where as uncomfortable as they are if they can if we can give say even just a week to do a proper diagnosis of what the microbes are in there I think that we could really use that to inform and actually make somewhat more tailored treatments for individuals that’s a hope what we’re doing in the meant in the in the near future I’ll try to summarize this one this time and not go on quite so much the intestine is six feet long six meters long excuse me the small intestine and I think what we need to be able to do is not just make drugs that can kill the microbe that can get through its biofilm but they can really get to where it is you know if you swallow anything it just moves through your gut it’s not really going to want to be in any one specific place and I think this has been a problem in the microbiome world in general which is how do you actually get compounds where you want when you want for the right duration of time um what we’re leaning more towards and what we’re working on and where I think we need to go is actually using microbes um to deliver what we’re interested in I’ll give you a specific example because it’s going to make the idea more I think easier to conceptualize we use vibrio cholerae as a model. Vibrio cholerae is a pathogen that specifically colonizes the small intestine. It doesn’t colonize the large intestine and even though it colonizes the small intestine it’s only certain locations of it and it can bury below the mucous layer it gets right up against your human cells and that’s where kind of it does its action. It is protected from many antibiotics because they either just kind of wash right past it or they can’t get to it so what we’re doing um is we’re focusing on the moment at a group of antimicrobials that are naturally produced that are called microcins um these are these have been known since the 70s but maybe I think maybe 10 or 15 of them are actually known and the tricky part has been finding them with advances in technology with algorithms that we’ve built we can now identify microcins quite readily microcins are extremely potent and extremely specific antibiotics so we have microcins for example that will kill vibrio cholera only and it won’t touch any other bacteria we also have microcins that would kill klebsiella or e coli um that won’t touch other bacteria they shouldn’t be harmful to other gut other health healthy bacteria in your gut so where am I going with all this what we’re looking to do is to take healthy bacteria that naturally want to exist in the small intestine in the same location that vibrio does and it’s not too tricky to find those we can then actually give those good bacteria the ability to produce these antibacterial peptides that will kill vibrio at that location so the goal is that somebody takes will swallow the bacteria they can go through your intestine and they will swim specifically to the location where vibrio is colonizing causing disease and when they get there they start to release the peptides that will kill vibrio I think that this type of approach is going to be needed because there is you know it better than I do rifaximin is this really broad spectrum antimicrobial that in a in a petri dish kills whatever bacteria you put in front of it yet when you put it in the gut even at I think the doses are something on the order of is it like 500 milligrams three times a day I think it’s quite high. Even then you don’t get these big effects in the like it’s it gets helpful for some folks but it’s not like your it doesn’t seem to have the same potency as it does in a dish. My bias I haven’t you know have not proven this in any way is it’s this challenge of when you take it orally it doesn’t really seem to go where you necessarily need it and we need ways of doing that not we need ways of not only killing the microbe we’re interested in with all of its biofilm and associated issues but we need ways of localizing it to that bacteria to that area where it can perform its functions there’s other ways we could consider doing this we work in antibody therapies and I think there’s an opportunity there. But I’m at the moment a bit bullish on the idea of using beneficial bacteria that already want to kind of be in that location to just go there naturally and start to release these antimicrobial compounds to hopefully get rid of the negative microbes

Sumit Khetarpal: Got it got it very fascinating so um how is this approach I guess when you talked about using bacteria as a delivery vehicle it sounds very similar to what I’ve seen people use bacteriophages for which are viruses that are used to deliver uh the drug that you want to deliver and I think I’ve seen a couple of companies take that route where they’re using bacteriophages how would this be a different approach

Bryan Davies: it’s similar and that it is targeted the difference for me comes really in twofold when you take a phage yet again like rifaximin or any other type of drug it doesn’t really care where it goes it just kind of flows through your intestine and does whatever it does it’s not going to try to specifically track to the location where the infection is and try to set up resonance other issues is that phage like other compounds can have trouble getting through mucus and biofilm and even when they do they not always but it’s not too hard for a bacteria to gain resistance to a phage pretty rapidly it’s not that we shouldn’t try to pursue um phage I just see them as not having the target specificity as well as kind of the duration of action that I want to clear and hopefully maintain clearance of a gut infection

Sumit Khetarpal: Got it. Excellent. Well, I think that brings us to the end of our talk we covered a lot of ground you’ve answered pretty much all my questions, so I want to thank you for your time and uh we’ll stay in touch.

Bryan Davies: Thanks very much I appreciate the opportunity

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