Science Panel - Harvard FUSION Symposium 2017
Thank. You very much. I, checked. After that very sobering, lecture, from Tony foul Chi the. Stock for Gocha which is the they, own the brand for Purell it's spiked, just. In the last few minutes. Was. Definitely a sobering, story, and and part, of the reason for bringing the group together, I want. To thank Len LaVon take very much for his support, of innovation. In this, community, especially in. Innovation. In spaces like this where the market may not be the driver. I've. Been in discussions, with Peter Barrett's about, extending. The levant. Nic life sciences fellowship, competition. To include graduates, of Harvard Medical School where we, obviously have a very very significant, number, of folks, who are interested in turning, their medical education into. Entrepreneurship. The. Control of infectious, disease by, public, health measures, clean. Water vaccines. Antibiotics certainly. One of the triumphs. Of modern, medicine. My. Grandfather, was a was a horse and buggy doctor, he. Graduated from medical school in 1912. And he. Practiced, in the pre-antibiotic, era I. Have. A bunch of his textbooks, and, at. The time the cutting edge was the germ theory of disease the, connection, between bacteria. And. Various, infectious, diseases, but, the textbooks. And my. Grandfather's. Notes talk. About filterable, agents, the, agents, that were so. Small that they passed through the filters that captured, the bacteria, these were these. Were mysterious, and. We. Now know these to be viruses, and not the topic of today's subject we. Appreciate, that, resistance. In in viral, populations, is equally, as concerning. As we've learned from. HIV. We've. Come so far since. My grandfather, practiced. Medicine. And. Indeed the development, of antibiotics, has been, one of the great. Life-saving. Measures of modern. Medicine, but. As we heard, an. Increasing, number of infections. The acquired pneumonia, tuberculosis. Gonorrhea. That are becoming harder to treat and the antibiotics are becoming less, less. Effective. And, we, see this in, longer, hospital stays. Dramatically. Increased costs. And. Indeed, increased, mortality so, the question, that we have is what do we need to do to avoid. Doctor. Foul cheese post-antibiotic Yura. What. Research, strategies, are going to lead to the, development of new classes, of antibiotics. And what are the challenges the. Harvard is a great place for this discussion we, have a rich. And deep history and there. Have been many important contributions, to microbiology. And immunology. Antibiotic. Clinical, practice. And, interestingly. Right, now at the Center for the. History of medicine at the Harvard, Medical School countway library. There's. A great exhibit on max Finland, he's. A graduate of the college from 1922. From. The medical school in 26, he, had a 50-year, career as a physician, as a teacher and investigator, he led lots, of path-breaking research, into. Pneumococcus. Into. Treatments. He. Researched the clinical pharmacology. Of many different antimicrobial. Agents, and he. Did this I think. In a very appreciable, in close, collaboration with, industry. So. He was at the time also deeply. Concerned about the overuse, of antibiotics and, he recognized resistance, to sulfonamides. Which. Which he characterized, in the early 1940s. So, today antibiotics. Researchers, will hear from the following panel spans. Many departments. Several, schools. We. Are tackling. This problem from, the perspectives, of biology, chemistry. Epidemiology. Evolutionary. Biology, and Public, Health among, others, and today's, science, panel features. Voices, who are representative, of several. Of those perspectives with. Panelists, hailing, from the department, of chemistry and chemical biology in the Faculty of Arts and Sciences, as well as, Harvard Medical School, and its affiliate, Boston, Children's, Hospital the. Moderator, of our panel, Jennifer Leeds has, also spent time at, Harvard Medical School she was a postdoc, in bacterial, genetics with, John Beckwith, which, is now the executive director, and the head of antibacterial discovery.
For. The infectious disease area, of the Novartis, Institute. For biomedical research I wish. To introduce, Jennifer Leeds Jennifer, good. Afternoon. So I am. Coming up here on the, heels of some pretty big names. I'm. Not a Dean and I'm, not an academic I'm, an industry, which, is like the bad-word when, I was, leaving Harvard. And. I decided to go into industry it was not. A very popular move I'm pretty. Proud to say that the group that I lead and the. Environment. For people who decide to go into industry has changed dramatically as well so I'm glad to see that just. To give you a little. Idea, of Who I am because I know many of you but not all of you so I'm a 16, year veteran of the pharma industry 15. Of those at Novartis. I've. Led the knob or antibacterial discovery, group, and. The clinical microbiology team. For seven of those 15 years that, I've been at Novartis, in, response to the growing threat, of antimicrobial. Resistance the niger antibacterial. Team has taken three novel. Nyberg, discovered, compounds. Into. Clinical development and hopefully three or four more on the way our group has moved since. 2011. To Emeryville California so, we were in Cambridge for nine years and now we've been out in Emeryville for seven we. My group has supported five in licensed, clinical antibacterial. Programs and we continue to support two. Launched. And post, approval commitment programs. And I also work very closely with my anti-infective, colleagues, in the Sandoz generics division on their response to the AMR crisis, today. Dive personally, evaluated, over 300. Anti. Bacterial microbiome and, respiratory opportunities. And that's. An early discovery through post approval, coming, from both industry and academia, so I've seen pretty. Much the entire landscape of antibacterial, programs. And my. Personal. Passion is to. Build high-value communities, and, through. Those to achieve. Success, through knowledge sharing and constructive, criticism and celebration. Of success so I see this venue as a perfect, opportunity to learn and grow together so I hope you'll all join me in ads asking, questions of the panel I have some questions that I've prepared myself but. I definitely, encourage everybody, to speak. Up with the questions that that they have as well I want, to quickly talk. To. You just very very briefly in a three, minute introduction to some of the topics that were not yet, covered. By. Dr., Fauci and others oh that's. Fine that's okay I can see so. Very quickly. That. Gonna go just. To remind everybody that. Antibiotics. Are among the most important advances. In the history of modern medicine we cannot do transplant, we can't do oncology, we can't deliver babies safely, we. Can't do cancer. Chemotherapy. Immunosuppressive. Therapy we. Can't do transplant. And any of these of these modern. Medical miracles. Cannot occur without, anti-infective. And that. Need is going to continue. I think, this fusion event talked a little bit about stem cell and regenerative medicine, a couple, of years ago and with. That progress. Will come the need for anti-infective. To support those those. Patients, as well. But. As we heard, the growing Emmett need, especially, the treatment of gram negatives is putting modern, medicine, at risk and. That is due to the increasing, numbers of resistant. Pathogens in, the population. As well as the, increasing prevalence of intrinsically, resistant. Organism so these are organisms that don't have to acquire anything. From the environment in order to.
Be, Resistant, to current, antimicrobial, therapy and. The. Impact of anah, microbial, resistance is, that fewer. Patients receive the correct coverage, those. Options, even when available are limited, and then, we have to resort to more, toxic agents like the poly mix-ins, this, increases prologue, length, of hospitalization. And of course higher mortality. So. Why is it so hard to find new antibiotics we heard a little bit about, the fact that we know that these organisms, often have 20-minute doubling times so, we're, constantly selecting for, new pathogens, the. Other thing that I just wanted to, up is that we also need to think about covering a relevant spectrum, and so. While there's a lot of enthusiasm for niche and single. Organism, agents there's also going. To be permanently. A need for empiric treatment as well because, impair treatment allows you to be able to treat before you have the. Definitive agent. Identified. So. When. We talk about a target, for. Antimicrobial, therapy we're really talking about a whole, multitude of targets that, may have different, sequences, and the different pathogens that are important for us to cover and then, even among the species that might have identical. Proteins. They, differ, in their insurance, that can acquired resistance properties. So when. You say e coli a coli is not one organism. You, have to be able to cover a whole spectrum of those. The. Other point. That I want to bring up is that antimicrobial. Drugs, are. Given at extremely, high doses so. We dose up to 12 grams a day of, antibiotics. And when, you think about that you're, talking about millimolar, c-max quantities. Of these drugs so, the. Solubility, limits, that we have to put onto these agents, the, selectivity, the plasma protein binding properties, these. Matter they matter a lot and so the chemical, space that we have to work in in order to get these properties to. Be correct to be able to provide safe and effective drugs, is is. Very, very narrow it's much narrower than it is in other fields just because of the concentration. Of those doses and, because. These doses are very high and the markets demand, a low price those cost of goods can, be extremely high as well so these are areas that we need to think about when we're talking about the. Properties and the business of antibiotics. As well as the science, and. As. We said the gram-negative is the most difficult I think some of our panelists will go into this a little bit more but, just to remind those, of you who don't work with Grandma nega's every day they have two types, of membranes one of them looks more like a human. Typical. Lipid membrane, and then the outer, membrane of the gram negatives are actually polar so. Trying, to get compounds. That can go through to very. Very chemically, distinct, property spaces is a, very very difficult and tall order. On top of that when you get a compound in of course these organisms evolved, to, keep compounds, out but, when they enter. Then they have you flex pumps that, are also evolutionarily. Selected, in order to rid the, bacteria, of anything that can slide in. Which. Is why we still work on beta lactams so. I. Know that there's a lot of kind of yawn when you talk about new beta lactams because why. Are we doing more beta lactams but I can tell you from experience that, there. Is an advantage to working on beta lactams for example even though it's a known class you, only have to get through one area, of entry so you go through the outer membrane and that's it these are relatively polar, agents, and the. High polarity, restricts, the access of those agents to mammalian cells and it allows you to have a pretty nice, selectivity. And. Limits, the off-target, tox. Profile we also understand, a lot about beta lactams we understand their pk/pd relationships, we. Understand their spectrum very well they, have a very low historical. Attrition rate so if you want to get new agents out you can work on a class like this and physicians, understand and like to use beta, lactams, so. The new agent that we have currently in clinical, development is ly s 2 to 8 it's a novel model back to M that we developed, manav. Actives are intrinsically, stable, to, metallo beta lactam aces like ndm-1, so. That. Is a class that is stable, to that class of beta lactam aces and then we made them stable. To the Sirian beta lactam aces so we have a single, agent, that, is resistant, to all four classes of beta lactam aces and that's in phase one. So. Our new agents going to solve this. Problem I think we've heard, pretty clearly, that the answer is no we have continuous. Selection we have shifts and demographics we, have more and more invasive procedures and, we have more and more people who are surviving at the extremes of life very, very young very, very old so.
This. Is not going, to be an area that is going to go. Away and it's going to be an area for which the demand is going to continue to increase. So. What's going to inform the approaches, what's. The medical need in 15 20 years what, are the relevant selection, pressures what, will be the role of prophylactic. And adjunctive. Therapies, will. There be real, beside diagnostic. And susceptibility, reporting, and you need both not, just diagnostic, you need susceptibility, testing will. There be routine therapeutic, drug monitoring and then are, we going to see in advance in new chemistry's and manufacturing, technologies, because this is really an area that I think is woefully underappreciated, by. The industry. So. Today we have a panel of experts who I'd like to invite, up now and. I. Think. That's the, end of my intro, and we'll move into. Hearing. From a, great. Group of. Faculty. You guys can find your seats and, some of what you're gonna hear today is going to be translatable, and testable in patients in the not-too-distant future and. I think that combating, antimicrobial, resistance is the wave of the future because. The. Advances in modern medicine has, to be the next frontier, we, have no choice we have to make this work there's a whole bunch of new ways and approaches to do that and sometimes, we just need to do something different but that requires a significant. Investment, of resources, and a, tolerance for a runway that is long, enough to, provide decision-making, data there, is no quick, and dirty with, these new approaches, and lockable, favor a prepared, mind, in. Order to describe. The, research that my lab undertakes, I want, to take one minute to remind the, non experts, about where, our current arsenal, of antibiotics. Has come from. In, the two decades following the clinical, introduction, of penicillin, in 1940. Virtually. All of our major classes, of antibiotics, were, discovered, these include tetracyclines. Macrolides. Cephalosporins. Rhythm. Ison's winco's, amides and all the others listed here, these, incredibly. Valuable. Natural. Products, the product, of perhaps. A billion years of chemical, evolution are. Really twofold gifts, first, they identify, the vulnerabilities. The targets, and, second. They provide lead matter with. Which to address those targets. I say, lead mather rather than drugs because, the natural products themselves are, seldom, effective. Drugs they they, many, of them are toxic poorly. Absorbed. And. Poor pharmacokinetics. They. Do form. Good. Starting, points for drug discovery. But. These molecules, did not evolve with, evolutionary, pressures, to be effective. In, humans so. The. Way that most antibiotics, have, been discovered, is by a process, known as semi, synthesis, where, scientists, have worked out how, to ferment, penicillin. And oxytetracycline, and. Erythromycin, on ton, scale and then, in very challenging, chemistry. Medicinal. Chemists, over decades have found ways to decorate, these molecules, and it is almost a truism, that by, chemically, modifying. These antibiotics, they can be made better, drugs, they, can be made safer. More stable broader. Spectrum. Better. Pharmacokinetic. Properties, but, this engine, is sputtering, to. To, an end there that really we've we've, just about exhausted, what, we can do through, semi synthesis, it is incredibly, challenging to, modify, a single. Position of a molecule, like erythromycin. But. Through semi synthesis, what, my lab has focused, on over, decades, now is, to devise, chemical. Pathways, to build these complex, scaffolds. From, simple industrial chemicals. We. Focused, on molecules. That, bind to the bacterial, ribosome here, are 13, different. Natural. Products, that through independent lines, of evolution have, all converged, on a single, target and I think that makes a powerful statement about how important, that target. Is. Here. Are six, natural, products, or molecules. Derived from a natural product that all target, the bacterial, ribosome and, you don't need to be an expert chemist. To, realize, that these molecules look nothing. Like one another and that. They are incredibly. Challenging. Structures, I think. If you had taken, a survey, in the mid-1990s, when, we began our research in this area and. Asked, chemists, about. These molecules, would there ever be a practical, in streel synthesis, of any of these I think, most chemists, then and perhaps many today would say no. And what, we have tried to focus on is to change. That and so I briefly want to tell you about two. Success, stories the tetracyclines. And the. Macrolides. We. Discovered, a process that. Allowed us to assemble. The. Tetracyclic. Skeleton, of, tetracyclines. From, these two simple building, blocks and these two simple building blocks were in turn made, through, short sequences, from industrial chemicals. With, this technology, tetra.
Phase Pharmaceuticals. Was, founded, in around. 2005. Or six and. Within a short period of time chemists. There had synthesized. More than 3000, fully synthetic. Tetracyclines. Most. Of them had antibiotic. Properties and, three of them are in the clinic, the. Most advanced, is this molecule, now known as a rava cycling. Which. With. A little bit of luck may, see approval. In the United States and in Europe in the coming year for the treatment of complicated, intra-abdominal, infections. This, molecule, is decorated. With a fluorine, atom at this position seven which. Is a trivial. Change. Except, that it would have been nearly impossible to. Do through semi synthesis, but, using a fully synthetic platform. That was fairly, straightforward, to do that, simple, change had, profound, consequences on. This molecule, as an antibiotic. It made it more potent, it made it safer, and it, holds the promise of oral bioavailability, all. Features, which molecules. Lacking, that fluorine didn't have. We. Then turned more recently, about five years ago our attention, on the macrolide, scaffold. Very, much like the tetracyclines. Discovered, within one year of one another both, tetracycline. And erythromycin, were launched as drugs within the, remarkably, short period of three years in spite, of the fact that they're both toxic. They're unstable, in the acidic environment of the stomach forming. Toxic, byproducts. And all, macrolides. Approved for human use are derived, from erythromycin. By semi synthesis. We set out to build the, scaffold. From simple molecules and last, year reported, that these eight, simple. Building blocks could be assembled. Through. A series, of coupling, reactions, in. Just 10 steps in an overall yield of 30 to 40 percent and. This. Contrasts. With the linear modification. Of erythromycin, say to produce the, clinical, candidates ELISA Meissen but this is a platform. And engine, for discovery, because we can modify the, scaffold, through. The building blocks or in through, intermediates, and chemists. At macrolide. As. Well as in my laboratory have, since made, approximately. 1500. Fully synthetic macrolides. And and. Our goal as a company was, to transform. Macro, lights which are historically gram-positive, focused. Agents, into. Gram-negative, focused. Agents, and here. Are data from three, different, chemically, distinct, scaffolds. Against. A variety of gram-negative, bacteria. I'll focus just on this Klebsiella, pneumoniae, since that was brought, up by a previous, speaker this is a current clinical isolated, as multidrug-resistant. And we, have mi seas of 1 & 2 micrograms, per mil against. That strain and you can see that neither erythromycin. Nor azithromycin, has any, activity. In that strain and and, we're just, getting started so we're very very excited, to move to become, a clinical stage company. Alright. I just put three, slides together to describe, the the program. That. My. Lab works on here at Harvard, so we're. Primarily interested. In, gram-negative. Bacteria. And in, particular. Were very interested. In a specific, piece, of the bacterial, physiology. Of the gram-negative bacterium. Which is the outer membrane and. This. Slide is just used, again. As Jem had mentioned previously, for those of you who weren't familiar with the anatomy, of. Gram-positive. And, gram-negative bacteria. The. Outer membrane is, the is really, the, piece of physiology, which. Distinguishes. The gram-positive from. The gram-negative bacterium. And i use this slide just to, point. Out that, the. Bacterial, world was divided. In two by Graham in the 1880s. And then it took about. 80 years before, we began to understand, the basis, of what, the Gram stain was. Distinguishing. Between so. It was only in the, 1960s. That we began to appreciate that, bugs. That didn't stain with the Gram stain had. An additional, second, membrane, that surrounds the. Peptidoglycan that. Gives these gram-negative bacteria. This. Additional. Tolerance. To many antibiotics, and. Actually. After, the, discovery, in the 1960s. Of the presence, of this second, membrane, very, rapidly, people, began to characterize. This. Outer membrane. Of the gram-negative, organism. And in, the early 1970s. It became clear, that this, was a very special membrane as Jen mentioned in her introduction, it's. The, cell surface of all gram-negative bacteria. Are primarily. Composed. Of, lip Apollo saccharide, which is a very unusual glycol. Lipid, which. Prevents. The, entry. Of large. Classes, of, antibiotics. That can normally, penetrate. The gram-positive cell. Membrane. The. The. Work that we've done actually, started, with a collaboration. Almost. 20, years ago now with merck we were looking. At, a. Class. Of vancomycin derivatives. Which we had synthesized, which, had. Some efficacy, actually. Among other things in, addition to treating em RSA they had, some effectiveness, against, gram-negative bacteria. And we went. To see if we could understand. How. They were penetrating.
The Membrane, and, in. The process, of studying these molecules, discovered, a machine, which. Is conserved, in all gram-negative, bacteria. And this machines job, is to, assemble the integral membrane proteins. Into. The outer membrane, of the, gram-negative, bacteria. One of the substrates, and the only essential. Substrate. That, it assembles, apart. From having, an offensive, beta-barrel, itself, is a. Protein. Which. Is. Responsible. Actually. For, assembling, the Lupo's polysaccharide. On the surface of gram-negative bacteria. And in addition, to, spending the last 15 years studying. The, machinery, that. Puts. Integral, membrane proteins, in the outer membrane we've. Also spent. A considerable amount, of time we've. Been involved in the discovery, and the characterization, of, the, machinery, that assembles, the lippel polysaccharide. On the cell surface of gram-negative bacteria. So, one machine makes, the other machine, that makes the membrane, and our, interest, has been primarily. Over, the last. 10. Years to, see if we can develop tools, that will allow us to study how, these two machines work, since. Obviously one. Strategy, for combating gram-negative. Infections. Would be to, interfere, with the proper assembly, of this outer membrane, make, the gram negative, organisms then. Susceptible. To large, classes of antibiotics, which are currently used to treat gram positive infections, and we do a lot of work in that in that area, okay. So. My. Laboratory works, on the bacterial, cell envelope. Primarily, in Grand positive, organisms such. As MRSA and the. The gram, positive, cells are all bacteria, are surrounded, by layers of something called peptidoglycan, is. And, so what's. Shown here, it. Are just sort, of it's, intended, to represent pep to a fragment, of peptidoglycan so, these chains, that you see our string are representing, strings of sugars, and they're, connected, by these peptide, cross bridges and for, the non-specialists. Bacterial. Cells build up very high pressures. Inside the cell that are pushing outward, on the membrane and so they need this, kind, of mesh, like framework. That surrounds. The membrane, to survive, because otherwise they would explode and so, a. Lot, of antibiotics, target, the Assembly, of the of peptidoglycan. The. Beta lactams, which have been mentioned a number of times are. A. Major class of antibiotics that that inhibit, them vancomycin. Is another clinically. Used antibiotic. That inhibits, those the. Biosynthesis. Of this and so what my, lab started doing a long time ago was developing, actual, methods. To study, the Assembly of peptidoglycan. And. We, extended. Our work to other components. Of the cell, the. Cell wall in grand positive, organisms, so. Tyco ik acids, are a major component of the cell wall and that's what these things are intended, to represent and, they're, very important, also for the survival, of the organism and. So. We. I. Started, out in a chemistry department, and we, started by developing, strategies. To make substrates. That would allow us to study these biosynthetic, pathways. Because, at the time I started, there, were lots of people working on antibiotics.
And Trying to find antibiotics, that targeted, this pathway and yet, people didn't actually know how the enzymes, in the pathway worked, because they hadn't been able to sort of assemble, the tools they needed and so tool, development obviously is a really important aspect of, taking. Antibiotics from. Sort. Of. Discovery. To. The clinic we, got to know what they do and. So we've. Characterized. A large number of antibiotics. That inhibit, peptidoglycan synthesis. This is a an. Antibiotic he characterized, recently, it. Targets, it's actually what's called a lipid 2 binding, antibiotic. And so those are a very diverse class, of antibiotics, that are made by. Lots. Of bacteria and, they primarily have ground positive, activity. And. And. They're of great interest, that types of acts bactin, was mentioned earlier but they're of great interest, because. Organisms. Tend to develop resistance very, slowly, to that class of antibiotics, and so of the questions, that I have for sort of company people who have maybe, looked more at this is why have they haven't these sort. Of progressed, further. Vancomycin. Has made it to the clinic but there's a large number of other molecules, that I think. Have. A lot of certainly. Potential. Another. Thing that my lab has done so as mentioned we we study Tyco ik acids, and and we have developed, methods we, try to develop methods to screen from what I call smart screens that allow you to get bioactive. Compounds that, target a particular pathway, very, rapidly, and so, I won't talk about how we do that but I will say that these are two molecules, that we found that inhibit, the taiko ik acid, pathway and we found them very, quickly without having to chase a lot of molecules that. Are. Sort of junk. Molecules. And. Currently. One of the things that we've become interested, in is how you can use sort of high-throughput. Mutant. Libraries. And next-generation sequencing. To, sort. Of predict. Antibiotic. Mechanisms, but also to identify new, vulnerabilities. In. Mersa but you could apply this to other organisms, and so, we have a transposon, mutagenesis, platform. Where we can make huge collections, of mutants and so transposons. Are just, well. They're just pieces. Of DNA. That hop, into, genes and, when they hop into genes they can inactivate, them but our transposon. Platform, has, these is, made with trans, with several different transposon. Constructs, so that we can not only in activate, genes but we can up regulate, them and so we make collections, of staph, aureus mutants, that are we, have five hundred thousand, mutants, in our population, and our. Constructs. Are bar-coded so we can tell which, transposon. Hopped, in where and the using next-generation sequencing. That's where you get the where and. So, we can then take these libraries. And treat them with different conditions a condition, could be an antibiotic. And we, look for, changes. In genes, and so each one of these black bar is intended, to represent where, trans where the transpose ones have hopped in and. Under. And so we get a lot in each gene and then under various. Conditions you. Get a loss, of, those insertions. In that, cell. That, mutant, and I mean you. Lose them from your your, population. And that tells you that that was that, those genes were really important, under that condition, and so we can basically look, at these, patterns. Of mutants. And see, what. I would call fingerprints. For what happens, if you treat with an antibiotic and that's how you get information on the mechanism of the antibiotic. But you also get information about, how what, the intrinsic, resistance. Factors, are to that antibiotic and so that.
Is Useful, and one of the interests, that we have is in. Using, this platform to, see if we can do, find, better, ways to. Use, antibiotics in, combination. And so the hope would be that we, can pick antibiotics. Where we can change the resistance, landscape. In, a way that extends, the lifetime of, the, antibiotic. And, we, would use that obviously in combination, with other kinds. Of information about, how resistance. Is emerging. Out, in the population so I think although we are sort. Of in a in some sense we're in it we need a lot of new compounds. We also have a lot of antibiotics, that currently work and we need to figure out how to use them in smarter, ways right. Because. I think that's where that's, one of the things that we can do to, kind of keep our arsenal. Alive so by way of introduction, my name is Ophir levy I'm a physician scientist. And. My. Little intro is, entitled. Bringing precision, medicine to the development, of anti-infective, x' I direct. A new program called the precision vaccines, program, at Boston Children's Hospital where. I'm a pediatric infectious. Disease consultant, my specialty, is taking care. Of children, with immuno, compromised, and severe infections, I'm also. In. The division of human biology translational. Medicine at Harvard Medical School and I also am a part-time employee of. The Food and Drug Administration I serve on the vaccines, and related biologic, products Advisory, Committee ver packed I fly to Washington DC, about once a month to sit on a panel voting. For example, on the latest, strains, of influenza to include in the vaccine, etc. So. I kind, of appreciate this. Very important topic from a variety of angles. So. In terms of background my. Laboratory, at Boston Children's is, focused. On the, change in the human, immune system across, age so, we model, age specific human, immunity, to, inform development, of novel anti-infective. Z' for, vulnerable populations, those, vulnerable, populations, include newborn, elderly, and immunocompromised, individuals. Their. Variety of approaches. We're interested, in for anti-infective, they, include antimicrobial proteins. And peptides those, are natural antibiotics. That are inside our white blood cells and expressed by our skin etc we're interested in adjuvant, molecules. That turn on an immune response and we're, interested in vaccines, and preventing, infections, as. A professional. From. My professional life as I mentioned I'm a pediatric, infectious, disease physician and scientist and my motivation really is that in, preventing, an infection, particularly. Nerney life and any stage of life can. Be life altering and, life saving. The. Landscape, us this was touched on by dr. Fauci, and by Jan as well you. Know the biomedical, effort there's, an effort now to make it more integrated, but at times it feels like the basic translational, and clinical are. Fragmented. There's, insufficient, knowledge regarding, antibiotic action. In the very young I confront, this as a pediatrician all, the time and it's not just the pharmacokinetics. Right how do you dose the drug how often do you dose it but it's also the pharmacodynamic. How the drug acts at a site of infection there's, misuse and overuse of antibiotics and, livestock we talked about that, insufficient. Pipeline was touched on and often. Reliance. To my opinion on sometimes some preclinical models, that may be poorly predictive. Often. Anti-infective. Development, does not take into account, differences. Between individuals. In, age sex, body mass index, immunity. Genetics, epigenetics all, of these can. Packt response. To an antibiotic or any drug impact, on addressing, a microbial, resistance and patients, include that, frequently, I'm confronted, by making clinical, decisions, based on incomplete evidence, base the, diagnostic, limitations, in terms of diet time to diagnosis, failure, to diagnose or incomplete, diagnosis. And limited. Assays to measure the presence of microbial, components so in my view it's not just killing the bugs but, often the bacteria, release, bacterial. Components, that signal inflammation, that can be harmful, there's. Limited preventive. And therapeutic options. In terms of susceptibility, drug, drug interactions, distribution. Penetration, of the drug. Now. This is a key, figure for. What motivates, our lab and this plots the infectious, causes of death in, the world by age so the y-axis is the number of infections. Causing death and the x-axis is the age of the population impacted. And as you see it's a u-shaped, curve so. Infections, cause death most frequently, in the very young and then, it rises again in the elderly and we view this as extremely important, and often overlooked.
In Bio pharmaceutical, development because. The types of infections, they're manifestation. And the way that antibiotics, might or anti-infective, zmei interact with the immune system can vary radically with, the age of the population, that's being targeted and this, is what we're talking about in bringing precision, medicine to, anti-infective. I. Recently. Reviewed, the area of how immune ontogeny, the change if the immune system with age impacts. Efforts to prevent infection, in early life whether, it's through maternal immunization. Whether. It's through breastfeeding and the breast milk includes a lot of immune factors that help prevent infection, whether, it's newborn or infant immunization, or, the use of probiotics I will. Point out that approximately, 11% of, the globe is born preterm and, among. Those preterm, infants, there's a heightened risk of infection, not, just in the NICU when they're in the NICU but, that increased, risk persists, until they're 18 years of age this, is a major population, that, we need to keep our eye on in terms of targeting anti-infective, 'z, I'll. Also point out that in the preterm newborn there's, accumulating, evidence that a brief, bloodstream, infection, with Staphylococcus. Non aureus, or, staph epidermidis which, is typically considered a less virulent bacterium. Can. Be associated, with inflammation, that harms the newborn brain so. The consequences. Of a bloodstream infection can be very different by age as well we. Also will. Point out that. Many factors impact, efficacy, of anti-infective. Including, vaccines there's. Increasing evidence that sex matters men and women may respond differently not just to vaccines. But. Have differences, in the way they clear certain drugs. Including antibiotics, we, alluded to age as a factor, we also point, out in the lower left panel that giving to, drugs at the same time is not equivalent to giving each separately, that there are drug drug interactions and, that, the more knowledge is needed about that also in the field of antibiotics, and that. There are regional, Geographic, or epigenetic differences that can impact a response to an antibiotic. This, slide got a little bit messed up but, it's. Meant to illustrate, a number of human in vitro platforms, we make use of in our lab these. Include, an effort to take human white blood cells outside the body and we, can screen using these platforms for anti-infective, --zf or agents that kill bacteria in, human blood and the, growth of bacteria is, very different, in newborn, blood versus. Adult blood because, of different immune factors we. Can also screen for agents that turn on an immune response and we, can also employ tissue engineering, to, model, eight specific immune.
Responses, In newborns. Adults and elderly individuals. We. Believe there's a paradigm, for using, precision, medicine in the realm of anti-infective, 's that this would include, proper. Preclinical, models to help the risk development, appropriate. Animal models that take age sex and other factors into account targeted. Clinical trials and the use of big data or systems biology approaches. I'm, Alex macadam I'm the laboratory, director at Boston Children's Hospital the microbiology, laboratory director so, that's the lab that. Receives all of the specimens, from the children cared for at the hospital, that are being tested for infectious agents, and we, test for those infectious, agents using a variety of methods, including, culture. Biochemical. Assays that some of you will have done in undergraduate laboratories. For example as well as mass spectrometry and, a battery of molecular. Assays as well, so. That's my primary job. I do some other things as well I do research on the utility of diagnostic, tests seeing children in sort of a broad way I, also do quite a bit in education, I have been the director of the microbiology, course for, the first. Year medical students, and the dental students at, Harvard Medical School for, about, a decade or so and finally. What I think landed me up here is that I'm the editor-in-chief of the Journal of clinical microbiology or. Journal some of you are familiar with and for, those who are not this is the leading journal in the area of diagnostic. Microbiology. It is the coca-cola of, journals, in this particular, little niche, of Diagnostics. So. The role of the clinical laboratory in. Opposing. Antimicrobial. Resistance, the emergence of animal grow bill resistance, is I think very, much underappreciated. And dr., Falchi I very much appreciate, you mentioning this and calling out rapid, Diagnostics, as an area that's. Required for attention. Right, now the, selection of antibiotics, what dr. Levey is going to treat his patient with depends. On many things including. The data generated, from the laboratory, and those, data are generated very, slowly so, this is a very optimistic portrayal. Of. The kind of information we would give over on day. Zero to one we might say we know the morphology of the organism, gram positive, versus gram negative what shape it is and that, would guide selection, of some antibiotics, but, it would probably be quite broad, meaning. That he would be choosing antibiotics, they would treat a wide variety of pathogens because. He can't narrow yet, the. Next day we might be able to tell him the species of the organism that's causing the infection and, the, day after that day two is, the, earliest that we will be able to say what, antibiotics this, organism, is susceptible, to and this, is absolutely, an Achilles, heel, in our. Efforts. To reduce. Antimicrobial. Resistance and development, of antimicrobial, resistance I see, this primarily, from my perspective as a journal. Editor this. Is an area where there is a major push right now to try to get more rapid Diagnostics. Not. Only as we've heard for detection, of microorganisms. But, for determining. What antibiotics. They will be susceptible to, so. Thank you all for the brief. Introductions, hopefully you have an idea now of who's sitting on our panel I have a whole list, of questions that I'm I'm happy to pose to the panel so. This, is open to the whole panel you, know a number of you may want to respond to this some of the questions are more targeted towards one individual. Or another but the first question I have is one. Mechanism for managing. AMR, which, is a term I prefer over combating, because I'm not sure we're going to combat much of anything I think we're gonna manage it is. To develop new agents with some regularity and, ideally. In advance, of high-need. So. From, a scientific, and clinical perspective, what. Should we be focusing, on to anticipate, the. Next unmet, need and then, what aspects, of Medicine, basic, science and technology, do we need to emphasize and, prioritize, to.
Ensure That we can meet those future needs and how does your work enable, that the. The slide with the 20 years of antibiotics. I know many of the experts in the audience want. To move on to new classes, of antibiotic. Antibiotics. And and abandon, those classes, but, a point I wish I had made is that these are underutilized, resources. Because. The vast majority of, those complex, structures, have never been tackled, adequately, by chemists, chemists. Such as myself and and. These, are incredibly. Challenging. Undertakings. It took us 10 years to develop a tetracycline. Synthesis, 5, years to develop a macrolide synthesis. But once these platforms. Are, exist. They, can be mined for decades and I and I imagine will yield clinical, candidates, for that period of time and so, I think the time is now, to. Have chemists, working on these fundamental, problem. With an eye towards practical, solutions, because. It's going to take years and and, frankly in my opinion the funding is not out there for, that amount I think that. One. Option, which we, take quite, often is, to, make. Second, or third or fourth generation. Antibiotics. Where, we, have some confidence, that, we. Already. Have a structure. Chemical matter that. Has. Some utility and, I think obviously, that has to continue. My. Own experience, is that if one looks at, the chemical, matter that's available to, discover, new. Classes. Of antibiotics. I. Think. At least as it relates to the treatment, of gram-negative, infections. There, is. Not. Enough, adequate. Chemical. Matter that. Can. Meet the criterion. Of being. Able to penetrate, the. Outer membrane. Of the gram-negative bacterium. So we, find when we do, high throughput screening, and, look, at hundreds. Of thousands. Of compounds. That, very. Very. Small. Numbers, of. Compounds. Are, even. Able to penetrate. Into. The the gram-negative, organism. And so. I think that what that means is that we're, seeing, that, a very. Very small. Fraction, of. The. Available chemical, space and we need. New. Ways of being able to generate. Chemical. Matter that has the, ability to penetrate I think that's the key problem, for treatment. A discovery, of new classes, of agents. A tree creme negative actually makes. An excellent point this in fact you're calling kinds Moser published. A great review article on this if you look at just say the log D value of, most, compound, collections, in pharmacy, I mean antibiotics, look nothing like other, drugs so. I guess for the audience. Um they're, what. They're talked about he's talking about is its, uses. Green chemical. Libraries, that you get from mostly, commercial, vendors, because as academics. Don't have access, to proprietary libraries. Not even or in the proprietary, I can tell them that even companies, right they buy compounds. And so the, compounds, that they buy are obviously, made, by people want to make a lot of compounds, and so they're they, tend to be, kind. Of flat and they're. Made sort, of using easy coupling reactions. And so, you need to get more sophisticated, libraries. There are some, libraries. That people, have made that are more sophisticated it's. Very hard, to fund follow-up. Studies, with those libraries, and so there. Are a lot of problems, so I think we now know how to screen, and. We know a lot about how to find compounds, but what we're finding tend. To be things that are just you, know they. Could be better and we could find more if we had better better, libraries. To work with so. Let me see if there's a question. One. And. This, is a follow up my, name is Brian Baker I on. A local, laboratory. For the Food and Drug Administration. And. Our, role, is. To respond, to public, health crises. And, outbreaks etc, so. When. There are. Crises. Like the. Scopes that are used in hospitals, reused. And, perhaps. Contaminated. Api's. Or drugs or any. Number of these things and we do trace back investigations. And we. Do analyses, on these in this, lab in Winchester. I'm. Curious. To how we might work together, better. To. Maybe be more specific about what we're finding in, the. Short term that could, curb some, public. Health outbreak. Faster. Because. Making. All the linkages to just. Identifying, you know that, to. Be more specific about the species for example, you've got this library of 3,000. Different. Alterations. To these things we, have whole.
Genome Sequencing, capabilities, but we don't talk. To one another about these libraries, etc and, I'm just curious as the. There's. Room I think to do that and and. We should think about I'd. Like to talk to you about how we might be more effective at doing that. Yeah. So one, of the things I think there that, the ability. To kind. Of look at whole genome sequences. Broadly, because there's a lot of them people are sequencing. Antibiotic. Resistant, organisms. At an incredible, pace and so you can see patterns emerging. In. Terms of how sort. Of antibiotic. An also track, the use, of antibiotics, in hospitals and correlate, them with those sort. Of changes. In the genetic backgrounds. But, what we don't yet, know is, how to then. Understand. What's, happening. In particular. Strain background, so easy even in the same organism, you can kind, of find that one. Variant. Of it will develop resistance to the antibiotic, X but never Y and this another organism will be developed resistance to, antibiotics. And. So maybe. If you could combine those, antibiotics. You, would be able to sort, of prove cup, two to. Prevent, or. Slow resistance. But, you then need to be too kind of people, like we need. To be put. Together with people of that information because what we can do is we can look at the vulnerabilities. In. Though. In particular. Types. Of strains. And. And try and figure out what's happening at a molecular level using. These big, mutant. Libraries, and so the combination, of that in community. Information, with. The. Ability, to kind of look. Sort. Of deeply. I. Think, would be really valuable and, so how does one do it that's, a good question. There's. A new. Memorandum. Of agreement between, Harvard, and the agency. And. I think we should explore perhaps. Through that vehicle how to. Look, at this particular issue. Okay. Question. From dr. Ellie yeah. The. Panel is focused on targeting. The microbe. I'm. Just wondering what about innovation. In a host response, ten shaking the host response you asked my photo in the myelin suppression, we've, had g-csf but, then, we can make IPS derive granulocytes.
Is There a role for i think, that's worth in in, chronic viral infection, obviously there's a robust. Biology, around t-cell, exhaustion and trying to overcome that yeah, what about yeah, so. So i was gonna say that that, this is really gonna take a multi-pronged, approach to, manage, antimicrobial resistance. Dr., Fauci mentioned immunization. And and that's really, key there. New vaccines, and development, a group a streptococcus vaccine. For example could theoretically, help, reduce use of antibiotics, in. That setting, and, of course we know that it's you know antibiotics. Are life-saving they're also altering. The microbiome, and they come at a cost we use them when we need to other. Examples of this immunization. Could also be passive immunization antibodies. We use for RSV, to prevent, in preterm infants, right they. Could also be passive, innate immunization. So for example, when. There's neutropenia, there's, deficiency. Of anti, microbial proteins and peptides from. The host there's. Already evidence in preterm newborns, that they are relatively deficient, in these natural antibiotics. And studies. Have shown that, if you give them for example bovine. Lactoferrin, orally. To pre terms you, then reduce necrotizing, enterocolitis, and, lay down sepsis, sepsis. In in preterm newborns, and that standard of care in some European, Nick use now in Italy and other places so. That is moving forward I was involved, in a very major effort, to try to develop a novel anti-infective. Derived. From neutrophils, bactericidal. Permeability. Increasing protein it's a neutrophil protein. That neutralizes endotoxin. The surface of the gram-negative and. And, that's one, of the most potent inducers of inflamation, known, to humans in, meningococcal, sepsis, which is an infection that can kill an otherwise, healthy teenager, in 18 hours there's, a huge amounts, of this toxin, poured into the bloodstream and, there. Was a phase 3 trial done that had a very naive, kind of design because you had, kids presenting, to a rural clinic in Texas with some lesions, on their skin and somebody may have suspected meningococcal. Disease they, get a shot of ceftriaxone you, killed the bugs and all, the antitoxin gets released and at this point the kids going on a medevac helicopter getting. To Dallas to the ICU and the distraught parents, are being consented, for intravenous. Infusion, of placebo. Or the neutralizing, epi. Protein, to neutralize endotoxin, this is published in The Lancet years ago it, was a randomized, placebo-controlled and. There. Was a benefit, shown, in the treatment group but it didn't hit its primary outcome, because, the overall mortality was, lower than predicted because. They had made an assumption, based on data from 3 years ago and the ICUs, had gotten better at, treating meningococcal, sepsis, but there was reduced limb amputation. In the treatment group etc that's a long and winding story, of a biotech, failure, but we can learn from the failures and I, believe, that in the right context. Passive innate immunization. In the, host who's going to benefit it's for the folks who don't have the, defense factor whether it's their preterm an oncology. Patient who's neutropenic, because of chemotherapy, etc so, I think there's an enormous potential, in that area, and. And also if you read the most recent reviews of sepsis which has really been a graveyard of, biopharmaceutical. Development, you're. Going to look and see that people are turning more and more to personalized, medicine we're going to have to define, subgroups who would benefit based, on host factors, and microbe. Factors, and that gets to the Diagnostics, as well so it's all connected and. I realize, you were asking primarily in the context, of therapeutics. But looking at the host response is also a very exciting area in Diagnostics, right now as well so, if, we can tell, physicians. That the patient has a viral infection versus. A bacterial, infection very, quickly after the patient comes into the hospital based. On the pattern of their host responds by looking at the RNAs or the proteins produced by the host response that, can lead them down the correct that way for therapeutics, as well. Samir. Mitra go3 biomedical, engineering Harvard I have. A question for the panel as dr., Fauci as well, so, there was a lot of discussion, about unnecessary. Exposure, of humans to, the. Agents, and just to deliver, antibiotics. Locally, let's try him first before, going to systemic route are, you referring to, infections. That are local. Meaning. Mucosal. Surfaces. So. Instead, of treating them systemically, should be first make an effort to treat them by, local, deliveries, so we are avoiding system, exposure, to antibiotics, so. Sparing, whatever the body does not have infection, why expose the body yeah. So, there, are topical. Agents, that are used for for, you know truly localized, infections.
There's. Also been quite. A bit of attempts. To treat wound diabetic, wound foot. Infections. And. Other seemingly. Localized. Infections, which actually, can become systemic, if not treated, effectively so, it, kind of depends on whether. You know for, a fact that something is truly, localized. Or, whether there's any risk that something is going to become systemic, so yes, if you have, clarity. That that you're looking at a truly localized, infection then, you don't necessarily need, a systemic antibiotic. But then that's also, not typically, prescribed. So, I am, I'm, agreeing with what you're, saying but I'm not sure well. Well I was, wondering are you alluding to like my next-generation technologies. Like nanoparticle. Delivery of antibiotics. Rebecca yeah yes, something like that yeah I don't know you know theoretically, it's exciting, I don't know whether there's been any technical, advance there you know so. The challenge is in knowing whether the infection is local, or having a technology, which can actually localize, the antibiotic. To the site I think, the pharmacokinetics. Have been challenging as well at least historically. Yeah. I mean if you look at there was a recent failure of, mackanin, that. Was thought, to be effective locally. And it turns out that it wasn't it, wasn't truly effective in a controlled trial. I went, I want to jump in for a for. One second, and then I see Jared because, there's always Jared. And. This was a question that I had, about the. Diagnostic, paradigm so. I, guess this is mostly directed to with. The current paradigm it's, it's difficult. To get diagnostic, platforms, to support new and niche. Molecule. Antibiotic, drugs, let alone modalities, that are quote not traditional, such. As phages anti. Virulence, compounds, biofilm, disruptors, compounds. Against hosts immune targets, and so. The question is from the perspective of the clinical microbiology lab. What. Scientific, advances, need to happen to support the appropriate, use of those agents and how can biology, and chemistry enable. Those advances. It's. It's, it's. Tough clinical. Laboratories, don't have, the bandwidth to develop, assays for the most part and, so we depend on manufacturers. For the tests that we use and in, the context, of antimicrobial. Susceptibility testing. Those, tests, are usually FDA. Approved. So. A manufacturer. Of a, novel, or new agent, needs, to keep that in mind as the develop the agent that there's going to be a need for susceptibility. Testing in the clinical laboratory and, for. The most part that's going to have to be packaged up as. An fda-approved assay. Otherwise, the hurdle, for the laboratory to. Bring the test in is simply too high and we end up sending it to a large reference, laboratory, or commercial laboratory, and that's a very slow process. So. I don't know that there's going to be good, ways to have, flexible. Agile. Testing. For susceptibility. Beyond, what's currently available. Because of the regulatory structure, over it so. For the chemists, and biologists, in the room do. You see any, opportunity, here, for helping in the diagnostic, world is that something you guys think about it all I don't, think any of the three of us think, about the Diagnostics. We are chemists, and there, are people who are thinking of ways of doing that.
In. Your department. Well. My, understanding, is. That there are technologies. Out there that have improved to the point that you would get a much faster diagnosis. But, hospitals, don't always take them up immediately, because the, economic. Equation. Doesn't make sense. Which. Is a shame, so I don't know how to crack that nut but I've, heard that said yes, I think you've heard it from me. That's. That's exactly right there, are faster, methods for diagnosis. And detection of resistance, but. They are prohibitively, prohibitively. Expensive. For. Clinical, laboratories, and despite. Arguments from, our. Colleagues. And manufacturers. That these will offset costs, elsewhere, unless. We can demonstrate that in a really robust, fashion hospital. Administration, is not going to go for it so, Jared, go Jared. Silverman. A Collider Biosciences. The. Panel, is composed, of the people that we might expect, to see interested, in this space we've chemists, we have microbiologist. We have infectious, disease physicians. What. Do you think you can do to. Find. Colleagues. In the broader Harvard. Community. Different. Disciplines, possibly. Not even non science, to. Convince, them that the most interesting. Problem, they could be working on is. In. Antimicrobial. Resistance. It's. An interesting one because we all have our slide deck and we can show slides about the burden, doctor, foul she had very compelling, slides I showed some slide about the age, and infectious. Deaths but. Moving, opinion. Or moving somebody getting somebody psychologically. Engaged isn't all about numbers, sometimes. It's anecdotes sometimes it's a personal experience so it's, it's a good question I'm not sure I mean other right answer yeah I mean it seems like it's the financial, incentive. That's the piece that complicates. The development, event, infective. 'he's that, it, would be, it's. It's, a challenge, I assume, when people come into a clinic, with an infection. You give them a generic, or you give them the first-line. Therapy. And then you go down the, line. Until, you find. A drug that works rather, than trying. To use expensive. Tools to, to. Sort of pinpoint the, the, the. Agent, that's responsible. I think, that. The. Challenge, in in trying to decide should we develop. A narrow spectrum or broad spectrum, antibiotics. Is all about financial, incentive, is election I'm actually thinking much more broadly, than this like how do you convince somebody who's not thinking about this to start working in this area infect, his child, during. The last few years. During. The last few years I was a keepest. We launched. Something we called praveen's, crazy hand-washing project. That. I won't go into except. To say that you know it turns out that the problem of hand-washing. Which. Is generally the subject, of let's. Say third-rate, research, in you know fourth-rate, journals is. Actually, amenable to some really, interesting, science, and the. Question, that stuck, in my head at that point was, you. Know if you walked onto the Harvard campus or the MIT campus and said anybody working on hand wash yeah, there. Would be zilch, if you. Said who. Thinks they could deliver me a device, that. Could sterilize, somebody's, hands in five seconds, or less I. Bet. You'd get some pretty intelligent. People. Thinking very creatively about. A problem, that otherwise, they would never have spent, any time on so. That one of the things I would I would suggest is, that there's. A huge, untapped reservoir. On, this campus, of people. Who've never gotten. Up in the morning and thought I could, be solving, a really important problem here, and, I think maybe one. Of the things we should be thinking about is how do we how do we get to that group and this, isn't then also just about therapies. It's. About prevention, it's, about how. People behave. Relative. To their you, know medical. Practice, etc. So. One. Question that I have, that. Goes back to something that Andy said is. That. If not already in use today many, of the clinical used antibiotics would, actually fail to meet criteria, for progression, if they, were identified, as hits because, of concerns about safety resistance, chemical properties, costs. Manufacturing, hurdles etc, so. The question I have is what. Criteria should we apply to, new antibiotics. So that we don't throw out the baby with the bathwater and what. Basic, basic. Scientific, knowledge and technologies. Do. We lack today that if available, could enable us to move forward with otherwise, challenging, targets and chemical, matter and how does your work enable that what. Well one thing I wanted to point out was that in, the 1920s, and 30s there, was a microbiologist. Named Theobald, Smith and he, talked about the Theobald Smith equation.
This. Equation was, meant to help you think about the magnitude of an infectious, disease in an, individual, and he, said it was proportional, to the number of infecting, organisms, you have more bacteria are gonna be sicker than if you have fewer bacteria it's, proportional to the virulence factors if the bacteria are secreting a lot of toxins you're going to be sicker. Than if they're not but, all of that is divided by the host resistance, so we. Encounter. That clinically all the time if we have an, immunosuppressant. Or. Somebody, preterm. We. Know the immune system is distinct, and we know that. Infections, can be first, of all we have to consider a broader range of infections, and we have to realize. That the anti microbials, we use may. Need to be given for a longer period of time to cure infection, and, so I do think that having, technologies. In the preclinical and that. Take into account the host population. That we're trying to address, could, be part, of the puzzle and. And, that that's not always, kept. In mind pediatricians. Have, a big beef on this because, a lot of the drugs we use at the hospital every day and children were, never really, licensed, their off-label, use in Pediatrics, because there wasn't the, evidence base in Pediatrics, that's improved, to the years because there have been government, initiatives, to, incentivize. More information, about use of drugs and Pediatrics when I show you the curve about. You know who's getting the most severe infections. You know the pediatrics, should be the first on the list where, we gather this information and by, the way the infant's spread that influenza, or RSV, to the grandparents, and then they get. Severe, infection so it's really as a pediatrician I have to put put that out there and. And and feel that the preclinical, consideration. Should keep the target population, in mind and that's in an era of precision medicine that that should be swimming. Upstream hopefully. So. From the chemists and biologists. What do you think about. Criteria. That we should be applying to, new. Antibiotics, considering, what the, criteria, were what what the properties, of the existing, antibiotics, are and what we've learned from, that I guess, my reaction to the question, is I would never want to do anything that would have, the feel of compromising. Safety I, think, that's paramount. I'd. Be curious to discuss, maybe offline, with you which classes, of antibiotics, would, not be approved in in, this day and age and suggest, that perhaps those would be targets, for new medicinal, chemistry, efforts in. Order to make them safe. It. Kind of depends on what the. Clinical, indication, is if you have a narrow spectrum, antibiotic. That's going to work to. Treat c diff infections. You can deal with poor bioavailability. Or, possibly, toxicity. Issues. Much easier, simply, because, you're. Gonna restrict hopefully. Where you give that agent. Maybe, you don't need bioavailability. Maybe, you. Don't need the level of, selectivity. That you need if you have to administer, a broad-spectrum. Antibiotic. So you. Can take chemical. Matter that, is perhaps poorer, in some respects, if if, you've, defined, a problem, where you. Can limit where you're going to administer how, you're going to administer the agent, so I mean I think it does depend, I think the reason people I mean, narrow, spectrum, antibiotics.
Are Becoming, much. More important, as resistance. Becomes, a bigger, and bigger issue because, there are simply less. Agents. That are available, and, and the markets become, reasonable. But I really, think that a lot, of it does depend, on a financial incentive we, develop. Broad-spectrum antibiotics. Because you, can make more money