ABX_history_transcpt

Hello, welcome to lecture one on the history of antibiotic therapy. My name is Russell Lewis, and I’m going to be taking you on a little bit of a tour of some of the history of antibiotic discovery, some of the key individuals from the empiric versus rational schools that led to early antibiotic discovery and development, then recognize some of the major factors that led to a decrease in antibiotic discovery since the late 1980s into the current period, and really examine why are some of the advances in medical biotechnology, such as the genomic revolution, have not yet led to an explosion of new antibiotics. And finally, we’ll discuss some of the economic problems that have led to the lack of antibiotic development in this sector.

So it’s important to start with the correct perspective that if we think about antibiotics, where do they come from and how are they used? Microbes have been using antibiotics and producing antibiotics much longer than humans. Of course, there are much more microbes than humans, over 6 trillion more microbes on earth compared to humans. That’s 5x10³¹ vs 6x10⁹. This is also reflected in the mass in terms of metric tons. Of course, microbes replicate much faster. This explains why they outnumber us by a factor of five times, by a factor of 10⁸. And microbes have been on earth for over three and a half billion years, whereas humans are around 4 million years estimated. So the experience microbes have with antimicrobials is considerably longer than humans. We have less than a hundred years experience. And this really creates some challenges when we think about using these drugs.

Of course, antimicrobials are used differently by bacteria versus humans. Bacteria release these components in the environment, usually a trillionth of a gram over a very small space. There’s minimal environmental exposure, minimal selective pressure. But in the case of humans, we’re often using milligrams to grams per day and patients not to mention the kilograms of use of drug in animal and food production and thousands of kilograms that are released in the wastewater. So while bacteria have used these compounds judiciously over millions of years, over billions of years, humans have used these in a much more ubiquitous and less targeted way. And this is probably why we’ve seen a resistance increase considerably as we’ve used these drugs in medical and industrial use.

So the source of antibiotics is really quite straightforward. We know that this is a reflection of chemical warfare that goes on in nature among bacteria, fungi, and some of our most important antibiotics come from actinomyctes, soil bacteria, or molds such as the penicillin mold that grows on a melon that was a major source of production of penicillin.

However, there is a sort of ancient histories of antibiotic therapy or antibiotic-like substance. We know that in China, there’s written records of moldy tofu used to treat inflammation and infection of the skin. Moldy bread was also used to treat skin lesions in Egypt, and the Greeks used myrrh, wine, and honey, or other caustic substances to treat wound infection. So there is this concept of sort of a antimicrobial-like drugs, even though the germ theory of disease did not exist, and these were not truly systemic therapies, but we can find this evidence of antibiotic-like use even in the ancient history.

And interestingly, insights into antibiotic use were also provided by this paper. The first paper was actually published in the 1980s, where investigators reported that they found evidence of tetracycline in the bones of ancient Sudanese, Egyptian populations from over 350 years to 550 year in the common era, so this is some of the time of Roman occupation in Egypt. And these initial findings that were reported in the 1980s were somewhat debated whether this really represented tetracycline in the bones of the Nubian population. So the archaeologists went back later, and this report published in 2010 actually dissolved some of the bones in hydrofluoric acid, and were able to demonstrably clearly demonstrate that the tetracycline was present in the skeletal remains of ancient population from Nubia. And it’s believed that this was because of fermentation of grains. Also, the Egyptians produced beer, so they may have been producing beer that was contaminated with anctinomycte that produced a tetracycline-like compound that was actually drank. And this may have had actual health benefits, considering that many Egyptians at that time would have died from infections associated with their teeth and common bacterial infections. So evidence of antibiotic-like treatment in even prehistory. So the modern history of antibiotics is generally credited with Paul Ehrlich and the birth of modern antibiotic discovery.

Paul Ehrlich was a pathologist and chemist who was developing methods for staining tissue and made it possible to distinguish between different types of blood cells. And this led him to devise a magic bullet hypothesis where he believed that if you can differentially stain human cells, then we might be able to find compounds that would stain or target bacteria and not human cells. So he undertook the first rational approach to screening chemical libraries to identify active antibacterial compounds. And after over 600 compounds that he screened, he identified a compound called Salvaracin in 1909 that seemed to have activity against Tryponema pallidum and thus became the first effective treatment for syphilis, arsphenamine. So basically this was the first approach towards sort of rational drug discovery and come up with the first effective systemic treatment for syphilis.

This was not a very nice therapy. It was quite toxic to administer and its safety really depended on the physician that was administering the drug because it had to be reconstituted and stir water and injected into the veins and into tissue. And if it extravasated in some cases, it would cause a severe tissue injury and liver damage. So if the compound wasn’t correctly prepared, wasn’t correctly handled and administered relatively carefully, then this could lead to serious harm to the patient, even though it did have some efficacy in treating syphilis.

The other major school of antibiotic discovery is linked to Alexander Fleming, who made his serendipitous discovery of penicillin in the 1920s. Interestingly, Fleming was a large part of his practice besides his interest in microbiology was his skill in administering salviricin to patients with syphilis. He was known to be very good technical person in doing these injections. So he had a profitable practice. During World War I, Fleming worked with a wound research laboratory and discovered that chemical antiseptics do not sterilize jagged wounds and that pus had antibacterial properties. So he was focusing after the war on studying leukocytes and antisepsis. And he actually discovered lysozyme, a substance that causes bacteria to disintegrate, but it couldn’t be isolated in sufficient amounts to show that it would be potentially therapeutic.

However, the famous story, as we all know, upon leaving cultures, auger plates on his bench top after going on vacation, he returned to find a penicillin colony, a mold that probably came from a laboratory downstairs and the staphylococci that were on the auger plates, the growth was suppressed in the vicinity of the penicillin colony. This phenomenon had actually been described previously, but this hadn’t been reported and systematically studied, but it could be claimed that Fleming was not the first person to make this observation. It was known that molds could produce substances that would suppress bacterial growth, but he began to study this more systematically and he made a report on the antibacterial action of cultures of penicillin, which he called the compound penicillin based on the mold, with a special reference to the use against B. influenza. So he actually envisioned this as possibly an antiseptic type agent, not necessarily a systemic agent, and he had a lot of difficulty purifying the compound so he could systematically study it. So he never did any work in animal models, but he did develop microbroth dilution testing or MIC testing to explore the activity of penicillin against various bacteria.

Now around this time, there was also work that was going on in Germany. Gerhard Darmajk was a investigator who worked in the IG Farben chemical labs and he was based on some of the work of Ehrlich. There was a lot of interest in can you find compounds that may have antimicrobial activity. So they were screening basically dyes for antimicrobial activity, and they discovered a new class of drugs, the sulfonamides, and the first compound was called Prontosil. Interestingly, it didn’t appear to be active in vitro, but when it was injected into mice, it was found to be active in vivo. And this is because Prontosil had to be metabolized to sulfanilamide, which is the basis of our sulfa antibiotics. Remarkably, one of the first patients treated with Prontosil was Darmajk ’s daughter, who actually contracted a severe streptococcal cellulitis. And we don’t think about cellulitis now as being a major cause of death, but prior to the antibiotic era, mortality rate could actually be as high as 15, 20%. And so his own six-year-old daughter fell down the stairs, holding a sewing needle. She developed a streptococcal cellulitis from the wound after the needle punctured her hand. And because he was utterly desperate when the doctor recommended amputation to save his daughter’s life, Darmajk decided to treat his daughter Hildegard with Prontosil, and she actually recovered and survived. But because of these dyes, she suffered a permanent reddish discolorization of her skin owing to the drug. As you can see the red color of the compound here. So this was the beginning of the sulfonamides in Germany.

Now, the rediscovery of penicillin occurred from the work of Howard Flory, Ernst Chain, and Norman Heatley in Oxford, who became interested in purifying and trying to develop the antibiotic, trying to develop penicillin as a therapeutic agent for bacterial infections. And this was the major challenge of purification and developing enough of the compound. So a lot of this credit actually goes to Ernst Chain and Norman Heatley for their ability to purify and develop a pure substance that could be actually tested in vivo. And what was recognized in some of the first animal experiments is the incredible power of penicillin. We see on the top panel treated with penicillin and controls all the control animals after they were inoculated with streptococcus, they were all very sick within hours of infection and died within 14 to 16 hours. We see a single dose, 10 milligrams, or multiple doses of five milligrams of penicillin, basically all the animals survived. We don’t see any crosses.

So this was incredibly encouraging, but the challenge, and this was at the beginning of World War II, was fermenting enough penicillin. And the initial idea was that, based on the idea of looking at bedpans in the hospital, you could develop these cultivation flasks for penicillin to try to produce enough of the drug to go into therapeutic trials. And Norman Healy, who didn’t receive the Nobel Prize in the end for this work, but was incredibly important in this difficult time when there wasn’t a lot of resources available because of the war, was able to develop ways of optimizing the production of penicillin to produce enough of the crude drug and gain samples with few impurities to develop and produce enough penicillin for early therapeutic trials.

One of the first patients who was treated with penicillin was a police officer in London who developed a very severe infection. It’s sometimes said after a rose thorn puncture. Others have said it was after damage due to the blitz, a wound that occurred during the blitz, but his name was, this police officer, his name, Albert Alexander. And if you read the description of his clinical course, it’s really quite impressive that he was admitted in 1940, with separation of the face, scalp, and of both orbits from a sore at the corner of his mouth a month earlier. Primary infection was staph aureus, secondary was strep pyogenes. He was initially treated with a sulfa drug. With no improvement, he developed a rash. He had multiple abscesses on his face and scalp. He developed osteomyelitis of his right humeral head. And he also developed an infection of the left eye, his cornea perforated. And this police officer, poor police officer, was quite sick and in the process of dying.

So he’s administered 200 milligrams of penicillin given intravenously, then 100 milligrams, three hourly intravenous, except for two intramuscular dosing. And he had striking improvement after a total of 800 milligrams of penicillin. The discharge on his scalp decreased, his eye improved, separation conjunctivitis, his blood tests improved, quite a remarkable turnaround. The problem was the penicillin supply was exhausted. After giving 4.4 grams in five days, although the patient felt much better, they ran out of penicillin. And he was then developing a progressive pneumonia with strep pyogenes and M. catarrhalis. And then he began, after being clinically stable for 10 days, he deteriorated with pneumonia and died. And his autopsy showed a typical picture of staphylococcal pyemia with multiple abscesses. So actually one of the ways to try to continue to treat patients was to collect their urine, to repurify the penicillin from the urine. But because of the challenges of producing enough penicillin, it was very difficult to do clinical trials for their clinical trials in adults. Although some studies were continued in pediatrics where less drug was needed.

Winston Churchill also developed pneumonia. He probably would have died, but his life was safe with sulfapyridine. So a antibiotic developed in Germany saved the life of the British Prime Minister during World War II.

The major change occurred when Flory and Healy traveled to the United States and they convinced the United States government and United States pharmaceutical manufacturers to invest in the industrial scale production of penicillins. This of course was also a major wartime of importance of allies that if you can produce penicillin, you can treat patients with bowel field wounds. And so there was a major investment in industrial scale production and optimization so that more drug could be produced and larger trials could be instigated. And what was important component of this is that no patent was given specifically to Oxford University. They basically gave away the discovery of penicillin. And so many companies were able to produce penicillin at the time. And this was always probably a sore point from the British perspective that this major discovery was given away for free, but it was very important for obviously humanity.

A very important female scientist also around this time, Dorothy Hodgkin began to study, who’s an expert in X-ray acoustography at Oxford University, finally discovered the structure of penicillin, earning her the Nobel prize in chemistry later in 1964. And this knowledge of penicillin structure allowed scientists to modify penicillin leading to the development of the semi-synthetic versions that we have today with improved spectrum of activity, increased stability and reduced toxicity.

But from the very beginning, resistance was a problem. And Ernest Chain and Abraham described very early an enzyme from bacteria able to destroy penicillin in as early as 1940. So as soon as the antibiotics were available, resistance was detected. In fact, we know that resistance probably existed prior to the clinical use of penicillin.

And since that time, we’ve been repeating history. After the introduction of new antibiotics, resistance develops relatively quickly for many antibiotics. It may be preexisting, the clinical use of antibiotics. While interestingly, there’s some drugs where resistance in terms of our ability to detect it seems to take a little bit longer. A drug such as vancomycin or polymyxin that maybe have multiple targets for interaction or act on the cell membrane, sometimes resistance is delayed. But the point is, if we look at the history of antibiotic development, resistance is always inevitable with our antibiotic therapy.

Another very interesting chapter that has an Italian flair is the discovery of cephalosporins. Giuseppe Bronzu, who actually went on to become the president of Sardinia and the mayor of Cagliari, was a epidemiologist who studied typhoid infection. And he noted that Salmonella typhi was not cultured once sewer water was discharged into the sea. He eventually isolated a mold. And a lot of people thought this was because the salty water was what was responsible for killing off Salmonella typhi. But he had the different hypothesis that it may be some type of microorganism that’s producing an antibiotic. And by doing screens, he identified the mold, cephalosporin, now known as acrimonium, from seawater near the effluent into the sea at Cagliari. And when he tested these in the laboratory, he noticed the cultures produced substances he named mycetin that were effective against Salmonella typhi to cause a typhoid fever. And this was important because Salmonella typhi produced the beta-lactamase. So this was a compound that was active against a gram-negative bacteria that’s producing a beta-lactamase. He wanted to develop these compounds, but he was not able to gain support from the Italian government. So he sent the fungus to Howard Flory at Oxford, who subsequently isolated cephalosporin C. And they patented, this time they patented. They did not give it away to the Americans. So this was the birth of cephalosporins, which became a major class of antibiotics. And this is all due to Giuseppe Bronzu.

The first effective therapies for tuberculosis are credited to Salmon Wakesman and his team, who were also a part of a group doing natural product screening, especially the actinomycetes. And during the 1940s, his team discovered actinomycin, streptomycin, and neomycin. So, especially by studying soil bacteria belonging to the streptomyces genus, were a very rich group of bacteria for producing antibiotics. And they were found to produce a wide range of antimicrobials, leading to a number of important compounds, especially for tuberculosis. Wakesman is also credited with the introduction of the term antibiotic. Even though the term antibiosis had been used many years, antibiotic is credited to Wakesman in describing this class of antibiotic therapy.

Interestingly, the introduction of streptomycin during the mid and late 1940s was a revolutionary drug for tuberculosis, especially if you look at pictures from England, children, especially in the North, who may have been in urban areas, maybe not have adequate nutrition, who contracted TB, were often sent to the country to breathe the fresh air, to try to recuperate from tuberculosis. And you can see why it’s called consumption in this picture. With the availability of streptomycin, the infection could be controlled and eradicated. And you can see the effects on this child’s weight after treatment of streptomycin. And interestingly, one of the first children treated with streptomycin was the drummer Ringo Starr, who was at a TB sanatorium and was treated with streptomycin. But one of the major activities in the sanatorium was to teach the children to play instruments. And Ringo Starr liked to play the drums. He didn’t like to play other instruments. So based on that, he became a drummer, and that’s how we have the Beatles, famous drummer, develop his skills, thanks to TB and streptomycin.

We often talk about this period from the 1940s up to about the 1980s being the golden age, maybe stopping in the 1970s as the golden age of antibiotic discovery. This is a period when the idea that you could screen soils, samples, and different bacteria and fungi for the production of new antibiotics would lead to novel compounds. And many of our antibiotic classes were discovered during this time, the tetracyclines, the macrolides, aminoglycosides. But once again, as resistance developed, we would simply, hopefully go on to discover the next new class of antibiotic agents. But by the time we’re getting into the late 1970s, 1980s, new drugs are not being discovered using this classic empirical screening approaches. And the reason why is there’s this, and since then, actually, going into the 1990s, there’s been a complete discovery void in terms of completely novel antibiotics. Yes, we are still having new antibiotics come to market, but most of these are modifications of previously introduced agents or have new beta-lactamase inhibitors or chemical modifications to overcome a specific resistance problem. We are not discovering completely novel mechanisms of action, which is a little bit surprising considering that of all the advances in the understanding of genomic sequencing and high-throughput sequencing and the identification of new, potentially new targets, you would think there would have been an explosion of novel mechanisms of action, but that really hasn’t occurred.

And so the question we can now turn to is why has new antibiotic discovery faltered?

Well, as you do more and more empirical screening over time, you start to rediscover the same things that have already been discovered. So the early 1940s and ’50s were a period when the low-hanging fruit were already picked . And now, as we’re doing screens, you have an increasing problem called dereplication of more and more of your time is dedicated to screening out or getting rid of the things that have already been discovered and trying to find a new discovery. And so it almost becomes cost prohibitive and time prohibitive to discover new antibiotics using some of these classic approaches.

Now, that doesn’t mean that there aren’t novel ways to get around this, go to new places where people have not done screening, new type of cultivation techniques that people have not done in the past, but the problem of dereplication, getting rid of things that you’ve already discovered becomes a bigger problem.

One of the ways the pharmaceutical industry got around this was to say, okay, we’re going to focus. We know that the most common targets are protein synthesis inhibitors, inhibitors of the bacterial cell wall. So if we focus on these targets, we may waste less time with dereplciation.. So try to get rid of these, make sure we’re not finding things that are just nuisance substances that won’t necessarily be developable as new antimicrobial agents. Or alternatively, you start with drugs that you already have, and then you modify them to make them more effective therapies. So there’s this idea that classic empirical screening for developing new antibiotics that drove much of antibiotic development from the 1940s, 1950s, 1960s, needs to shift to more rational discovery to overcome this work of dereplication. And that basically, because most of the useful antibiotics we discovered from natural processes came from drugs that targeted cell wall protein synthesis. Now the idea is, well, let’s just develop assays or screening approaches that focus on the cell wall and protein synthesis. And this could basically help us get rid of this problem of dereplication.

The other approach of course though, is then to modify existing antibiotics or scaffolds to overcome resistance. So the first drugs, the first cephalosporin that were discovered by Bronzu, developing it into first generation cephalosporin, second generation cephalosporin, third generation, fourth, fifth generation, to overcome resistance problems, to broaden spectrum of activity, to address key clinical needs. The same is true with beta-lactamase inhibitors.

We have the suicide inhibitors like clavulanic acid, tezobactam, sulbactam. These have now been developed and modified to overcome carbapenemases in many cases. And we have some very interesting beta-lactamases on the horizon.

And also of course, drugs like macrolides that have been developed from erythromycin to clorithromycin, tetracyclines have gone from tetracycline to mycocycline, to tyrocycline, to erythromycin, and more recently, other tetracycline-like compounds with activity against multi-drug resistant bacteria. So this has been a very important approach for addressing our unmet needs, but we still have a need for developing novel, completely novel agents.

Fluoroquinoloness have also followed this path Naldexac acid, to ciprofloxacin, to levofloxacin, moxifloxacin, and this has continued. But the industry was becoming a little bit tired of this approach getting into the mid 1990s, late 1990s, that just completely reiterating old antibiotics that may only have a relatively short half-life until the next resistance mechanism comes along.

Could there be another way to improve this? And probably the major breakthrough was the sequencing of the bacterial genome, such as Haemophilus influenza in 1995, published in Science. And the idea here was that now we can probe the entire bacterial genome, identify targets unique to Haemophilus, or maybe even unique to multiple bacteria species, or across all bacteria, and develop specific targets to inhibit these pathways or gene products that may have lethal effects in the bacteria that would not be predicted to have effects in humans. So this was thought going to be the major way we’re going to discover antibiotics in the future. And the reality is tons of investment went into developing programs based on genomic-based discovery in the 1990s. Up to the 2000s, but really very few novel agents were discovered. And the crisis began to get worse. We also began to see increasing antimicrobial resistance really increase with the spread of extended spectrum beta-lactamases in the 1990s on plasmids among Enterobacteraceae. And of course, increasing resistance among methicillin-resistant Staph aureus.

So in some ways, biotechnology has failed us in some ways of developing new antibiotics. And one of the most frequently cited papers that discusses this issue was by Payne and colleagues. It was published in Nature Review’s Drug Discovery in 2007. This was individuals who were involved in a major discovery program by GlaxoSmithKline, which at the time was one of the major companies invested in a genomics-derived target-based approach for screening new classes of antibiotics. And basically in this article, they share their experience of evaluating more than 300 gene targets, 70 high-throughput screens over a period of seven years, spend millions and millions of dollars and essentially found relatively little.

The key points that were raised by this paper of why antibiotic discovery, why this initially did not lead to an explosion of new antibiotics, is that by doing these genetic screens, they basically had a bias towards identifying compounds that inhibited a single target. Well, if you inhibit only a single target, there’s going to be a high risk of rapid resistance development, especially if you only need one small mutation or that resistance to develop. They often found that their compounds they’re identifying also had a bias towards human eukaryotic targets. So there was some toxicity potential that was higher using the genomic screening-based approach. One of the biggest problems though that wasn’t recognized is that once they identified a target through genomics-driven approaches, they would then use available chemical screening libraries that they had in-house to look for inhibitors of this target. And most of these screening libraries were basically composed of lipophilic compounds that had limited structural diversity.

And even though they would find an inhibitor, it wouldn’t be, it would work in a test tube, but it wouldn’t necessarily, it would work in inhibiting the target, but it wouldn’t necessarily penetrate the bacterial cell wall or it wouldn’t necessarily be a good drug for developing as a drug in humans. So there was a problem with the chemical screening libraries. They weren’t really optimized as libraries to develop new antibiotics, even though you could find inhibitors of targets that were identified. So this is why many new drugs did not come out of these screening approaches.

Investigators often identified compounds that looked like they killed in a test tube, but in reality, they act more like detergents. So really, they didn’t find very many, anything truly novel. One of the major problems, if you look at what they did find, they would find drugs that had activity against gram positive organisms, but the major medical need is in inhibitor, discovering compounds with gram negative activity. And once again, the problem is the libraries that were used to screen these targets. Once the targets were identified, were compounds that were not optimized for penetrating the gram negative cell wall, and certainly were not optimized for good oral bioavailability. So it was sort of a mistake. And that was recognized that a major emphasis has to be placed on using better screen, better libraries to develop this.

Probably this in retrospect is not so surprising. I mean, if you think about the natural antibiotics, those low hanging fruit, they were initially discovered. These were compounds that were developed over billions of years of evolution. It’s very difficult to improve upon nature. If you look at, for example, a compound like vancomycin, this is not something, this is not a chemical structure that would be in a typical chemical library of a pharmaceutical company. The natural products tend to be much more complex structurally. They tend to interact through several, multiple, several different target binding sites. And this interactions, these complex interactions that evolved over billions of years leads to antibiotics that act exquisitely in a selective way for pathogen targets versus the host.

So if you’re just doing a screen single target, it’s probably too simplistic and you’re not going to come anywhere close to the elegance of evolution over billions of years. So that approach is not going to lead to a new vancomycin.

This slide also shows just how far off the antibiotics fall versus what’s typically in a chemical library that was being screened against targets. So all these gray dots in the back represent the compounds in the screening libraries. And then the blue and red data points represent antibiotics that are actually clinically used. And you can see the important point here is that most of these antibiotics that have gram, especially antibiotics that have gram negative activity are way out in the extreme in relation to things that were typically being screened in pharmaceutical companies in the 1990s and 2000. So it’s pretty clear why you’re not going to discover new gram negative antibiotics. And some classes of antibiotics, for example, aminoglycosides are not represented there.

However, we should point out that it’s not as simple as just finding a perfect drug with a molecular weight of 500 that has this certain hydrophilicity. It’s really, there’s variation among different gram positive versus gram negative. That’s not surprising because of the difference in the bacterial cell wall, but also even among gram negative species, there’s a difference in drugs that have activity, for example, against haemophilus influenza versus pseudomonas aeruginosa and Klebsiella pneumonia. So the idea that you’re going to do a genomics based approach, identify a target, do a screen, identify a single compound that inhibits all gram negatives is a really incredible, challenging problem to overcome scientifically and requires a lot of thought.

So there was a lot of failure in the 1990s and 2000s. A lot of lessons were learned from this and especially looking at gram negatives, how you penetrate this outer membrane layer that excludes hydrophobic compounds, but then reach the inner membrane targets where the penicillin binding proteins are, overcoming the effects of beta-lactamases and efflux pumps that also exclude hydrophilic compounds is a very difficult challenge in terms of medicinal chemistry. So even finding compounds that will penetrate once you have a good inhibitor is a major issue.

So you may look at this and say, well, okay, why don’t we just focus going back to natural product screening? And once again, the problem is de-replication, but there’s many reasons to think why we should continue natural product screening because once again, we can take advantage of this evolution. The easy things have been discovered, but if we can search in a more intelligent way, maybe we can find natural products that have been selected over billions of years of evolution for antimicrobial activity. It’s also been estimated amazingly that less than 1% of prokaryotic and less than 7% of fungal strains have been isolated or cultured.

So this has been a major focus of some research groups to isolate unculturable bacteria, previously unculturable bacteria, such as deep in the soil, deep in the ocean, maybe in outer space for compounds. Do they produce antimicrobial like compounds that could be used and developed for antimicrobial therapy? Natural products, you also, when you’re banking on billions of years of evolution, you end up with more complex drugs that usually have a density and functionality and inhibits multiple different targets simultaneously. And interestingly also, natural products usually are not metabolized as rapidly or metabolized in the same way that sometimes the single target inhibitors previously from the pharmaceutical compounds are. So they tend to, these drugs, the natural products tend to have superior pharmacokinetics and they’re not metabolized by cytochrome P450 enzymes. So nature just doesn’t make as many inhibitors as cytochrome P453A4 substrates as when you’re starting with a chemical library that’s lipophilic and building blocks. And we have developed better ways for isolating and overcoming the de-replication problem.

However, targeted screening still could be very important as a rationale approach to develop specific inhibitors. There’s been massive advances in synthetic biology, combinatorial biosynthesis, pathway engineering, and of course in chemistry development of an antibiotic like scaffolds. So you can argue we need to do both, both natural product screening, but also targeted screening because 30 years of failure of developing new antibiotics have given us knowledge of ways to overcome problems like bacterial cell penetration, overcoming efflux, trying to develop new rules to help guide drug design specifically for antibiotics and using better libraries to screen targets when they’re identified. So I think that there is a potential of both targeted screening and natural product screening to lead to new antibiotics in the future. Of course, there are also alternative strategies that have been discussed outside of classic antibiotic therapy, adapting antimicrobial peptides from nature, even things like venom from wasps or bees has been modified or to develop antimicrobial activity like compounds. There’s interest in developing monoclonal antibodies, although the antibodies by themselves tend to be more successful therapeutic agents for neutralizing toxins or virulence factors. And there may be approaches including antibody, antibiotic conjugates to help deliver antibiotic therapy specifically to pathogenic bacteria.

We all know about bacterial phage therapy, the potential promises and challenges of this therapy. There’ve been some amazing case reports of success. The challenge in clinical trials is developing standardized cocktails, the production of the compounds, stability, developing the right cocktails to overcome resistance. So there’s a lot of work that’s being focused on bacterial phage therapy and its potential to use probably in combination with antibacterial therapy.

What about genomic approaches using antisense based antimicrobials or compounds to reverse or silence resistance mechanisms in bacteria? These things have shown a proof of concept of efficacy in animal models, and maybe it could be a therapy in the future. Maybe we can use an antisense based therapy to turn off beta-lactamase production, for example. And of course, vaccination and immunotherapy. Vaccination is important for many of our common bacterial pathogens. There are some challenges with some of our most problematic multi-drug resistant pathogens like hasinidobacter, pseudomonas, but there’s always a potential for vaccination to be explored as a way to limit drug resistance and to work in combination with our antimicrobial therapy. So these are approaches that are going to be pursued.

But the last message I wanna leave you with is the economic issue, because it now takes between 10 to 15 years to develop a new antibiotic. The failure rate for new antibiotics is about 95% in terms of you identify a candidate lead, developing it into first in human studies, phase two, phase three, phase four, coming to the clinical market, more than 95% of discovered drugs fail. And the costs are astronomical, over $1 billion. So many large pharmaceutical companies have actually left the field. It’s too high risk, too low return by the time you developed a new antibiotic. In many cases, you only have a couple of years left on the patent to recoup your investment. So it’s much more profitable to develop drugs in oncology, dermatology, other disease areas. Antibiotics are not a profitable field. And so for this reason, many large pharmaceutical companies have left the antibiotic development field. Now, most of the work is being done by small biotechnology companies that hope to be bought out by large pharmaceutical companies when they have a promising candidate. But this is a big problem for us with increasing resistance, lack of development of new antibiotics. This can have enormous public health consequences and could reverse our ability to safely treat infections and also perform very high risk procedures in patients.

So there has been a discussion of this, what’s the problem with the economics? If the issue is we need to sell antibiotics, if you think about when a new antibiotic is approved, what do we do? We tend to put it on the shelf and not use it. And this is bad for the company that developed it because we wanna preserve that antibiotic. So this idea of having a link between how much you use the antibiotic and its sales and how much profit is made is thought to be a major stumbling block to new antibiotic development. And some people have said we need new models such as a “Netflix model” were we should paying a subscription price whether we use an antibiotic or not- i.e. delinking the prince paid from the amount consumed….. And this way we could incentivize new antibiotic development but we will not be overusing the antibiotic and promoting resistance.

There’s a very nice video explainer on this from the Financial Times. I’ll leave in a link below, but the link here is also on this slide.

But interestingly, even some federal governments have began to look at subscription models, the UK and Sweden, and even in Italy, a new fund has been established for basically the purchase and subscription of super antibiotics. The idea is that the Italian government will pay a fee to have access to a certain amount of antibiotic for multidrug resistant bacteria. It will be classified as a reserve antibiotic, will not be routinely used or widely used, but even if it’s not used, will pay money to have a financial incentive to have these antibiotics development. So sort of Italy is developing into the Netflix model, investing in the Netflix model after the 2025 GA Health Summit.

So in conclusion I hope this presentation has provided you with some understanding of the parallel problems of increasing antimicrobial resistance and the lack of novel antibiotic development. There’s been classically two schools of antibiotic discovery, empirical versus rational. Each has their converts, both are important. Both have given us useful antibiotics.

Actually the empirical classic screening approaches is responsible for the majority of our clinically used antibiotics.

And even though biotechnological advances have given us many new impressive medicines, especially in oncology, it’s largely failed to deliver new antibiotics, especially for gram negative pathogens. But there is potential to learn from these failures over the last 30 to 40 years to hopefully maybe improve rational drug discovery.

But one of the things we clearly need to fix are the economics and development of new approaches to ensure that antibiotic research is funded, that antibiotics are brought to market, and there is a financial basis to sustain antibiotic development and availability so antibiotics are available for future generations.

Thank you for your attention.