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History of Antibiotics
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0:00
What would you consider the first antibiotic? When I asked you this question on the community tab, most of you said penicillin. And while Fleming’s discovery of penicillin in 1928 is probably the most famous antibiotic story out there, the real answer takes a little more nuance to understand. This is the first video in a multi part series about the history of antibiotics, and in today’s video, we’ll ask — what counts as the first antibiotic?
0:22
But before we get into the story, we need to define antibiotic, and to do that, we need a crash course on bacteria. I want you to think back to those diagrams of animal cells you learned back in 7th grade. You mighty remember that human cells have a fatty cell membrane with a couple of proteins and pores on the surface to let stuff in and out, and inside the cell we’ve got a bunch of little organelles, like mitochondria and ribosomes.
0:41
Bacteria have a lot of similar organelles and cell membranes kind of like ours, but there are some important differences. Number one, we’re in a domain eukaryote, meaning the DNA in our cells is wrapped up in a structure called a nucleus. Bacteria are their own separate domain. And they’re prokaryotes, meaning their genetic material isn’t surrounded by a nucleus. Big difference number two, in addition to cell membranes, bacteria also have cell walls around them, which are made with
1:06
a chemical called peptidoglycan. It’s kind of like a chain link fence. The squiggly lines here are the peptide parts and, the round balls are the glycan parts, or sugar parts. Bacteria are constantly rebuilding and repairing their cell walls — they need them to survive. And number three is the sheer diversity of bacteria — they can come in all kinds of shapes and sizes They can be rod shaped bacilli, sphere shaped coccus bacteria, spiraled and a bunch of other shapes.
1:33
And some bacteria have differences in their cell structure that make them vulnerable against some antibiotics but unaffected by others. Like the germ that causes tuberculosis has mycolic acid in its cell wall, so it’s unaffected by penicillin. But we’ll talk about that later in the series.. Also, not all bacteria are pathogens — meaning they cause disease. We actually need some bacteria for good health, like in our gut microbiomes.
1:54
Ultimately, the goal of an antibiotic is to use the differences between human cells and pathogenic bacteria to make medicines that harm them but not us. Unfortunately, defining antibiotics is kind of tricky. The word has meant different things throughout history, and kind of depended on who you’re talking to. Like when you’re talking to your doctor today, antibiotic just means a medicine that kills bacteria. But historically, the term antibiosis means any life that destroys other life to support
2:19
its own — literally, anti-biosis against life. The term popped up in scientific writing in 1889, but the more we learned about bacteria, the fuzzier this definition became. Bacteria might harm each other through chemicals or as a parasite. There are a bunch of ways something could be antibiotic. So in 1942, a research team at Rutgers University lead by Selman Waksman focused the term on the chemical substance doing the antibiosis.
2:44
An antibiotic inhibits “the growth or the metabolic activities of bacteria and other microorganisms by a chemical substance of microbial origin”. That’s the definition that caught on, so that’s the definition we’ll use. It’s a chemical that destroys bacteria and is made by other microbes. Now, the old school healers we’re talking about in this next section didn’t know about microbes but there is evidence that some of them successfully treated infections using antimicrobial substances.
3:08
And so, with our new vocabulary, we can finally look at what ancient doctors used to treat infections. First up, multiple societies used some variation of mold. Imhotep in Ancient Egypt documented the use of moldy bread to treat infected wounds, which was then passed down through the rest of Egyptian medicine. And healers in central Asia used a moldy paste made from chewed barley and apple that they applied to wounds.
3:30
Now there are plenty of molds that create antibiotic chemicals like we’ll see in the penicillin episode. And molds are made of microbes, so mold meets our definition as a source of antibiotics. But the big question is whether these molds would’ve actually cured an infection, since the naturally occurring concentration of antibiotic in the molds was probably too low to be effective. The second big contender is a drink that humans have been making for millenia and involves
3:53
a yeast, which is a microbe too — we’re talking about beer. And while alcohol will kill bacteria, that’s not what I’m getting at here. The best evidence comes from research published in the American Journal of Physical Anthropology in 2010. Scientists analyzed skeletons dating back from about 350 to 550 CE from the Nuba people of modern day Sudan. They found evidence of some compounds in their bones that seemed a lot like the anitbiotic
4:15
tetracycline, hinting that they consistently ate something in their diets with the antibiotic in it. Tetracyclines are made by a genus of bacteria in soil called Streptomyces, which the Nuba people used in the production of their beer. But to clarify — this wouldn’t be like the beer like you’d get today — it was more like a sludgy, thick paste that you ate instead of drank. That 2010 study found so much tetracycline in their bones that the author concluded these
4:37
people intentionally kept the streptomyces as part of the beermaking process, whether they knew it treated infections or not. Either way, it was an antibiotic chemical made by a microbe. It counts. Honey was another big wound remedy around the world, again, with good reason. It’s acidic, can dehydrate bacteria and has a couple of compounds that show antibacterial properties in vitro, meaning in the Petri dish.
4:58
Manuka honey in particular has gotten attention because it has a type of chemical called methylglyoxal. And this chemical has been shown to kill bacteria on actual human wounds, not just in a petri dish. Over in China, practitioners of Traditional Chinese Medicine used different herbs and plants against infection, some of which do have measurable antibacterial properties. Like they used a plant called Artemisia annua, or sweet wormwood, against a bunch of diseases, including fevers.
5:22
And in the 1960s and 70s, Chinese scientists found that preparations of the plant could actually kill malaria in mice, but not reliably. But after a little more work to find the active ingredient, chemists isolated and named artemisinin in 1973 and now it’s a WHO recommended treatment for malaria. Unfortunately, it’s tough to say whether the whole plant would’ve actually treated malaria two thousand years ago, especially since we’re still not totally sure how artemisinin
5:46
works at the cellular level. But it led to a modern antimalarial, so half credit. Over in Europe, scholars were putting together their own antibiotic remedies. Bald’s Leechbook from the tenth century described a salve of wine, different types of garlic, onions, and ox bile meant to treat lumpy eye infections. These lumps were probably styes, which are infections of an eyelash follicle, usually with staphylococcus aureus. And there’s a decent chance the salve actually worked.
6:11
A 2015 study replicated the recipe and found that it killed MRSA in a petri dish, and a 2018 study concluded it was probably because of a chemical called Allicin in the garlic. But the disease that really got healers to think about infection was syphilis. I mentioned this in the miasma video, but since syphilis is spread through sexual contact, it got doctors to consider whether invisible, miasmatic vapors actually spread disease or not.
6:35
So at some point in the 1500s, doctors start trying out heavy metals like mercury for syphilis. Usually in the form of a mercury salt applied to the syphilis wound, or by breathing in vaporized mercury. Did it work? Well, they thought it did. In high doses, Mercury is a diuretic, and since syphilis is sexually transmitted, these doctors thought more frequent urination might clear out the contagion from the victim’s penis. Also, pretty exclusively penises.
6:59
Doctors weren’t exactly looking for treatments for women yet… But the side effects were rough. Mercury caused everything from kidney failure to neuropathies to death from toxicity. And it stayed popular for years! Around this time in 1640, a man named John Parkinson wrote a book called Theatrum Botanicum, a 1700 page history of plants around the world. Some of them I’ve talked about before like the anti swelling effects of foxglove or the heart rate effects of belladonna.
7:24
But Parkinson also references how moulds could be used to treat syphilis. He says ”Those bakers that will use the decoction of Hoppes, to mold up their bread, that make thereby their bread to rise better and be baked the sooner; Clusius reciteth the manner of a medicine used in Spaine, by women leeches, to cure the failling of the haire, caused by the french diseases in this sort”. Basically, female healers in Spain used mold to treat the French disease, which is what they called syphilis.
7:48
…well, the French didn’t call it that. Now even when we get into the 19th century and start to understand how germs cause disease, we still don’t get antibiotics right away. In the 1840s, Ignaz Semmelweis from Hungary showed how washing your hands with soap before delivering babies reduced infections of the mother. But soap doesn’t kill bacteria, it just removes them mechanically, so soap isn’t an antibiotic.
8:09
Then in the 1860s, Joseph Lister started using carbolic acid before surgery to clean wounds. But carbolic acid killed everything. It’s not just antibacterial, it’s antiseptic. We’d still need to find something that selectively killed germs without damaging our human cells. Alright, so that’s a lot of things that don’t quite count as antibiotics. We know that humans from history could treat infections, but depending on your level of pedantry, we had like maybe like two antibiotics? Mold and beer.
8:35
Where are we going here? In the year 1860, a French chemist was looking at a sample of pus from an infection and noticed that everything from the pus to nearby tissue was tinted blue. He figured that the bacteria excreted some kind of pigment, and did a few experiments with it before concluding that the bacteria could actually use the pigment to change colors like a chameleon. These days we call that bacteria Pseudomonas aeruginosa, but back then it was known as
8:57
Bacillus pyocyaneus, and the pigment as pyocyanin — pyo for pus, and cyaneus for blue. And some 19th century scientists concluded that the blue color meant the bacillus was overpowering the other germs in the infection. That the blue color was evindence of antibiosis. In 1899, a pair of German scientists named Rudolf Emmerich and Oscar Low wondered if they could use this bacteria to fight off other bacteria. So they isolated the Pseudomas aeruginosa from an infected wound, and mixed it up with
9:26
a bunch of other pathogens and found that it lived while the others didn’t. In their paper, they credit the antibiotic effect to a “bacteriolytic enzyme”, meaning a protein excreted by one bacteria that can lyse, or break open, another bacteria. So they killed the bacteria with chloroform, filtered it, and created their own medication that they called pyocyanase. The suffix -ase just indicates it’s an enzyme. It wasn’t, but they thought it was.
9:49
In the paper, they go on to describe two big experiments: the first was their rabbit model. They took 6 rabbits and infected them with enough anthrax bacilli to kill them easily. Then they gave three of them pyocyanase and left the other three as controls. The controls didn’t make it past a few days while the treated ones lived. Next, the in vitro experiments. They were able to use pyocyanase to kill the bacteria that cause diphtheria, staph, and
10:13
the plague, although they were less successful against typhoid and cholera. But overall, big success. Doctors started using Pyocyanse in local hospitals soon afterwards, and before long, other companies had come out with pyocyanase mouthwashes and eye drops. Even better, the original pigment, pyocyanine, was eventually found to be an antibiotic too. Which means, according to our definition of an antibiotic from earlier, that pyocyanase became the first antibiotic in 1899.
10:38
Waksman, the scientist who coined the term antibiotic in the 40s even calls it out by name. It’s a substance that kills bacteria that’s made by another microbe. Check. Unfortunately it was also super toxic in humans. Like doctors tried treating infections with the live Pseudomonas bacteria, but it attacked human tissue as badly as it attacked the infection. And when scientists tried to isolate and administer pure pyocyanase, it often just didn’t work.
11:02
You know how certain foods are marketed as antioxidants? Well pyocyanin is the opposite. It causes oxidative stress in certain cells, and that interferes with how the cell makes energy and transports substances across its cell membrane. That’s what makes it so toxic to our human cells, and why we don’t use it any more. So pyocyanase was the first antibiotic by Waksman’s definition, but like, it comes with an asterisk. It was an antibiotic, but not a useful one.
11:26
We’d still need something that selectively killed bacteria but left human cells alone. By the mid 1800s, scientists knew there were all kinds of microorganisms, from the ones that caused infections to the ones just hanging out in nature. But to make a good antibiotic, you need to be able to stop disease-causing bacteria and leave healthy, human cells alone, which means you need a substance that can get in to cells. And that’s where dyes come in.
11:48
In the 1850s, a British chemist named William Perkin created this purple fabric dye based on aniline — a byproduct of coal tar.He was able to create a bunch of other colors with it too, so aniline based dyes exploded in popularity after that. And German companies were especially interested in aniline production, including a company that becomes very important in the next video — Bayer. By the 1870s, half of the world’s dyes came from German companies and by World War 1 90%
12:15
of the dyes in the world came from Germany. And these dye companies ended up making a bunch of other chemical products like cosmetics, fertiziliers, and of course, medicines. But first, they had to figure out how dyes might be useful. One of the guys who gets super into dye chemistry was a Danish microbiologist working in Berlin named Hans Christian Gram. Gram was interested in bacterial pneumonia, and to study it, he’d have to look at a sample of bacteria under the microscope.
12:39
The thing is, it’s really hard to tell anything apart in a drop of raw bacterial culture — everything’s kinda transparent. So to make the germs more visible, he added a dye, which bumped up the contrast. But after trying this with other kinds of germs, he noticed that some bacteria took up certain dyes while others didn’t. This eventually became the Bio 101 favorite, the Gram stain procedure. It’s changed a little bit since the 1880s, but basically, you put a sample of bacteria
13:03
onto a microscope slide, kill them it with a little bit of heat, and add a blue or usually violet colored dye. Then you add an iodine solution to fix the dye, which gets into the cells and binds to the original dye so that it can’t get wash away that easy. At this point, all of the bacteria have been dyed violet, regardless of what type of bacteria it is. But then you wash the sample with alcohol, and some bacteria will lose their dye and some will keep it.
13:25
Anything that kept its violet color is called Gram-positive, anything that lost its color is called Gram-negative. And this is the most important part of this procedure. Remember how I said that bacteria have cell membranes and cell wells? Well not all cell walls look the same. Gram positive bacteria have a single layer of inner cell membrane and a thick peptidoglycan cell wall around it. Gram negative bacteria have an inner membrane, a thinner cell wall, and an outer membrane around that.
13:53
When you first add the purple dye, all the bacteria get stained equally, but then when you wash them them with alcohol, the outer cell membrane on the gram negative bacteria dissolves, and takes the primary violet stain with it. At the same time, the alcohol tightens up the Gram positive bacteria’s cell walls, which keeps the dye from leaking out. Now you’ve got some violet gram positive bacteria and translucent Gram negative bacteria.
14:15
At this point, scientists will add a fuschia colored counterstain to get those Gram negative bacteria to pop out a little more. Like here you can see the violet Gram positive staphylococcus aureus, and pink Gram negative E coli bacteria. That’s the point of staining — you can more easily tell the difference between bacteria that seem really similar to the naked eye. But at the time, Gram didn’t know why some bacteria took the dye and others didn’t,
14:37
and we wouldn’t really know until electron microscopy came out in the twentieth century. But clearly there was some kind of physical difference between these types of bacteria that we might be able to use in medicine. And I’m going into so much depth with this because we’re going to be talking about Gram positive versus Gram negative bacteria a lot throughout the rest of the series, but also because this same dye industry gave us new antibacterials that actually worked.
15:00
This is Paul Ehrlich, a German doctor who hit the scene when the dye industry was exploding in popularity. And he noticed the same thing that Gram noticed, but for anatomy. When you actually cut open a cadaver, especially one that’s a couple weeks old, everything is some variation of beige. It’s nothing like the color coded anatomy charts at the doctor’s office. So Ehrlich thought that if he could combine his knowledge of dyes with his knowledge of
15:22
anatomy, he might be able to make some structures visually pop out better for dissection. And he had a couple big successes. Like he found that nerves could be stained with a dye called methylene blue and used that technique to eventually find the blood-brain barrier. He also found different staining techniques for red blood cells and white blood cells, and a better way of staining mycobacterium tuberculosis, the germ that causes TB. And there was one big takeaway from his early work.
15:45
Dyes could be selective. They might stain some structures and bacteria but not others. Fast forward to 1891, and Ehlrich got a job with none other than Robert Koch who at this point, was the leading infectious disease researcher in the world. And while his colleagues were working on vaccines and antitoxins, Ehrlich wondered if he could apply his background with dyes to pathogens. Like if some dyes get into pathogens but not human cells, then maybe some kind of chemical
16:09
could selectively kill bacteria and leave human cells alone. He called this kind of treatment a magic bullet, and he got to work right away. That year, he experimented with methylene blue as a malaria treatment and was able to treat 2 people with it. But it never really took off since a drug called quinine was so much more effective. Unfortunately, at this point Ehrlich contracted tuberculosis and had to take a few years off work to recover.
16:31
But when he got back, he started a systematic research project to see which dye might be his magic bullet. In 1902, Ehrlich and his postdoc, Kiyashi Shiga, started a series of experiments which involved infecting mice with a type of protozoa called trypanosomes and seeing if any of their dyes could treat them. But since this kind of science was brand new, they had to start from scratch and test each dye — one by one.
16:52
And in 1904, they felt like they’d found a winner called trypan red....but then they noticed the trypanosome developed resistance to the dye and killed its host anyway. So that one wouldn’t work. Luckily, a few months later in 1905, infectious disease doctors published research where they used a form of arsenic called atoxyl to treat another trypanasome disease called sleeping sickness. The drug had the side effect of wearing down the optic nerve, which left some their test
17:16
animals blind, so atoxyl itself wouldn’t be the magic bullet, but it got Ehrlich’s lab to think about using arsenic. Now, they thought atoxyl was an arsenic based anilide, a derivative of aniline, the inspiration for the dye revolution we’ve been talking about. But Ehrlich and his colleagues figured out that atoxyl was a different type of arsenic compound, which meant they could modify it in different ways than anilides.
17:38
And if they could do that, they might be able to make a successful antibacterial after all. So they went all in on arsenic. They tried Acetylatoxl, but that made the mice run around in circles because the drug damaged their vestibular nerve. Then they saw that Arsenobenzenes weren’t as toxic, but not as powerful against the germ. Eventually they found a compound called arsenophenylglycine which was effective against the microbe and wasn’t too toxic. At least in mice.
18:03
But they noticed something else — this compound was effective against spirochetes, or corkscrew shaped bacteria. And coincidentally, some researchers had just found out that it was a spirochete that caused one of history’s most worrying diseases and one we’ve talked about already today — syphilis. Because even though it was the twentieth century, doctors were still using mercury to treat syphilis. So the syphilis researchers got in touch with Ehrlich and said “hey, we heard about your
18:28
arsenic research, and we think these microbes are really similar, so maybe some of your compounds will work on syphilis too”. And in 1909, a Japanese scientist named Sahachiro Hata, came out to Germany to work with Ehrlich. Hata had found a way to infect rabbits with the rabbit version of syphilis, which gave the team an animal model to study the disease with. So Ehrlich had him go through the old arsenic compounds and see whether they worked in this rabbit model.
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And by later that year, Hata found that compound 606, or arsphenamine, worked well in his rabbit syphilis models. It attacked the spirochete and left host tissue alone. But since so many of their arsenic compounds showed such bad side effects, they were super cautious with compound 606. They did a bunch more animal trials to make sure it was both safe and effective before beginning human trials at local hospitals and clinics.
19:11
Those clincal trials seemed promising so in April 1910, Ehrlich and Hata presented their story and early clinical results to a conference of doctors in Germany. That led to even more clinical trials and a huge interest in this new drug, which meant they’d need some help with production. Luckily, Ehrlich had built some contacts in the pharmaceutical division of a German dye company called Hoechst, so when his lab all of a sudden needed tens of thousands of doses
19:34
of this drug, they were the natural partner for production. Hoechst marketed the drug as Salvarsan, the arsenic that saves. And it was an amazing financial deal for everyone involved. Syphilis was everywhere in Europe at the time and within a year, Salvarsan became the most prescribed drug in the world. And Ehrlich became a superstar, and even got a Warner Brothers’ movie made about him in 1940. I’ll actually link the trailer below, it’s campy and I love it.
19:58
But as always, the hype was short lived. As Salvarsan went from an unknown drug with handful of users to a blockbuster drug with thousands of users, more reports of side effects started popping up. Ehrlich’s lab looked into it and noticed that Salvarsan tended to break down into toxic chemicals when it was exposed to air for a long time, or when it was dissolved in the wrong pH. So they modified Salvarsan into NeoSalvarsan, which they released in 1912.
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It was a more stable compound that could easily dissolve in water. This finally replaced mercury as the standard of care for syphilis, but, coming back to our original question, it still wasn’t technically an antibiotic. Salvarsan killed a spirochete, which is a bacteria, but it wasn’t produced by a microbe, so it doesn’t meet Waksman’s definition. But there were some important lessons from the Salvarsan story that ultimately led to the antibiotic revolution.
20:45
The first idea was the whole magic bullet thing. The idea that you could selectively kill some cells and not others. The second takeaway was the idea therapeutic index for antibacterials, basically the range between the minimum effective dose and the highest tolerated dose. And finally, Ehrlich formally documented the idea that some microorganisms could become resistant to antibiotics…. but when is that ever gonna be an issue?
21:07
In the end, Salvarsan had too narrow of a use case to change medicine by itself. Syphilis was common, but there were lots of other deadly pathogens out there that Salvarsan didn’t treat. Luckily, the next chapter of the antibiotic story gave us a much more useful tool against way more bacteria… it was the miracle cure of the time, and we’re still not talking about penicillin.
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