We've known about Antibiotic Resistance for over a CENTURY

I saw the article on how we've been warned about climate change for 36 years, and couldn't help but draw attention to this little nugget. We've known about antibiotic resistance since 1907.

At the turn of the last century, a man with a passion for fabric dyes got into the microbiology business and not only discovered antibiotic resistance, but used that discovery better understand how cells interacted with their environment.

A dye works by chemically binding to the surface of whatever you want coloured. In the industrial era, advances in chemistry meant that a whole slew of new dyes came onto the market. Why is this relevant for our story ?

Who is Paul Ehrlich?

Microbiologists had a problem. They couldn't see bacteria very well. Not just because they were mall, they had pretty good microscopes by this point. Their problem was that most things under the microscope were colourless. This is where dyes came in. Wilhelm Freidrich von Gleichen ha been the first to use dyes on hard to see cells. But he only had natural dyes at his disposal, and they weren't very good. The field hadn't advanced much further by the time microbiologists like Robert Koch had begun investigating bacteria in earnest. But Koch had the good fortune to hear about a man who could solve his problem.

Paul Ehrlich published his first paper about the discovery that aniline dyes were uncannily good at staining different cells, and his lament at how microscopists never used them. This brought him to Kochs attention, and the two eventually became friends early on in their respective careers. After Koch announced his discovery of the tuberculosis pathogen, within a day Ehrlich was telling him how to improve his techniques. The two became fast friends.

Ehrlich dyed all sort of different cells with different dyes, an he was particularly captivated by a strange effect. Some dyes were good at dyeing some parts of cells an not others. The "chromosome" is so called because it showed up very well with some dyes. Other dyes barely had an effect on some cells. There were some dyes that attached very well to bacteria, but not to any other types of cells.

Why did some cells take up more dye than others?

Ehrlich believed that the dye molecules attached to certain "receptors" within cells. These were present in some cells, and not others. Chromosomes acted as "receptors" of certain dyes that weren't present in other parts of the cell. Dye molecules that only stained microbes must therefore have "receptors" for dye that weren't present in other cells.

Ehrlich struck on the idea that if he could take dyes that stained a microbe, and attach a poison molecule to them, he had viable way of killing bacteria off without harming a human host. He termed these chemicals "Magic Bullets".

The Discovery of Antibiotic Resistance

While he was working on this problem that researchers at the Liverpool School of Tropical Hygiene, Anton Breinl and Harold Wolferstan Thomas, discovered that a compound known as Atoxyl, though to be non-toxic for humans, could kill off trypanosomes. From 1906, a number of expeditions to Africa took it with them to protect themselves from the Sleeping Sickness caused by these organisms. Robert Koch used it to treat patients on the shore of Lake Victoria. As a result, Atoxyl grew in popularity.

By this time, Ehrlich had already developed his first compound. He named it Trypan Red, due to it's colour, and success for treating mice infected with trypanosomes. Whilst this was useful as a proof of concept, Trypan Red only worked against the types of trypanosomes that infect mice, but not those which attack humans. It was while he was working on this that he first noticed that trypanosomes would eventually develop resistance to it. In fact, when he tried out other chemicals, like Atoxyl, he found that the Trypanosomes would inevitably develop resistance.

But Ehrlich wasn't disheartened by this finding. Far from it, it actually helped him prove his ideas of "receptors". By this time, he had a veritable library of different molecules he could give to cells, organised by shape and structure. There were some compounds which tended to kill off microbes. But when microbes became resistant to one compound, they became resistant to all of the others with a similar structure. This meant that the receptors were actually binding to dyes based on their shape. Antibiotic resistance shed a new light on how cells interacted with the chemicals and poisons they encountered.

But his discovery put him on a crash course with Koch, who was already embattled over Atoxyl. You see, that miracle drug had turned out not to be so miraculous. To his dismay, he'd found that one Atoxyl's side effects was blindness. Further study in 1910 would go on to show that patients were no better off using it than without medication. Adding to this failure was Ehrlichs findings that some trypanosomes became resistant......well you can't blame Koch for wanting to repeat the experiments himself. When he did, he used much higher doses of the drug than Ehrlich. It was for this reason that he didn't detect antibiotic resistant microbes, and thus began a drawn out disagreement. One which Ehrlichs nascent theories on antibiotic resistance could not withstand.

Ehrlich believed in a single path to resistance via the mutation of a single receptor. He had no idea that microbes could actually adapt to antibiotics in multiple ways, and this often scuppered attempts to test his theories properly. The weakness of his initial theories meant that his actual observations were sidelined. Koch suggested that the appearance of antibiotic resistance was merely a theoretical effect, only seen rarely in the lab, and that attitude stuck. Even when antibiotic resistance did come to be recognised, it would initially be dismissed as a curiosity that would only pose a theoretical threat to clinical practice. Funny how things can change.

References

  • Gradmann C. (2011). Magic bullets and moving targets: antibiotic resistance and experimental chemotherapy, 1900-1940, Dynamis, 31 (2) 305-321. DOI: 10.4321/S0211-95362011000200003
  • Gradmann C.(2009) Exploring the 'Therapeutic Biology of the Parasite' Antibiotic Resistance and Experimental Pharmacology 1900-1940 presented at Circulation of Antibiotics: Journeys of rug standards, 1930-1970
  • Titford M. (2010). Paul Ehrlich: Histological Staining, Immunology, Chemotherapy, Laboratory Medicine, 41 (8) 497-498. DOI: 10.1309/LMHJS86N5ICBIBWM
  • Casanova J.M. (1992). Bacteria and their dyes: Hans Christian Joachim Gram, Historia de La Immunologia, 11 (4) DOI:
  • Ehrlich P. Address in Pathology, ON CHEMIOTHERAPY: Delivered before the Seventeenth International Congress of Medicine., British medical journal, PMID: 20766753
  • Kaufmann S.H.E. (2008). Immunology's foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff, Nature Immunology, 9 (7) 705-712. DOI: 10.1038/ni0708-705

Shameful portions of this article were self plagiarized Originally blogged from at defectivebrain.fieldofscience.com from the final part of a longer three part series. For the full stories- Part 1, Part 2, Part 3