Mistakes Happen

As a researcher, I believe a clean, organized workbench is a hallmark of an excellent researcher. To my advisor’s utter bemusement, that somehow hasn’t translated to my own bench. Sir Alexander Fleming, the English scientist who discovered penicillin, would certainly understand because he was a bit disorderly too.

Before leaving for a relaxing vacation to the Suffolk countryside, Fleming left his petri dishes on the bench. The bacteria growing on the plates could wait, he thought. Upon returning, he looked at the Staphylococcus aureus bacteria on his plates and noticed something peculiar. One of his plates had been contaminated – something other than Staphylococcus had taken root. Interestingly, the area immediately around this mysterious microbe was void of bacterial growth (image below). And then, like a crack of lightning, it all made sense. The mysterious microbe was producing a chemical that was killing the bacteria! Over the months and years that followed, Fleming et al discovered that the mysterious microbe was the fungus Penicillium notatum, and the chemical it was producing was the antibiotic penicillin. The penicillin had diffused into the surrounding media, creating a bacteria-free zone (called a zone of inhibition). The Staphylococci, being highly susceptible to penicillin, was stopped in its tracks if it got too close.

The Golden Age of Antibiotic Discovery

Fleming’s discovery changed the field of medicine forever. Previously, bacterial infections were a death knell. In World War I, thousands of soldiers who were not killed by bullets and bombs succumbed to infected wounds. Treatment with penicillin was exceedingly successful. Governments around the world began production of the drug. By World War II, this “wonder drug” was being widely used on the battlefield and in hospitals throughout Europe.
Following this initial discovery, scientists reasoned “if penicillin could kill some bacteria so easily, there must be other antibiotics out there waiting to be discovered.” And so began the Golden Age of Antibiotic Discovery (~1940-1965). Pharmaceutical companies started culturing fungi and bacteria en masse looking for more antibiotics (image below). The pharma company Eli Lilly even had the bright idea of asking Christian missionaries to bring back soil samples from every exotic place they visited. In fact, a sample from Borneo led to the isolation of Amicolatopsis orientalis – from which vancomycin was eventually extracted. Who said religion and science couldn’t get along?

This plug and chug approach was wildly fruitful, and led to the discovery of most of the antibiotics we use today – erythromycin, tetracyclin, vancomycin, cephalosporin, etc.

Low Hanging Fruit

Things were going swimmingly after penicillin was discovered. Many more antibiotics had been discovered, and it felt like the danger posed by bacterial infections had finally been neutralized. Little did we know, nature can throw the meanest curveballs. The bacteria that we were indiscriminately treating with antibiotics started showing resistance to the drugs. The more we used an antibiotic over time, the more ineffective it became. We were witnessing a phenomenon that continues to plague us to this day – antibiotic resistance. (Curious about how antibiotic resistance works? Check out my blog post Fighting the Resistance.)

This, however, wasn’t the end of our woes. The rate at which we were discovering new antibiotics started plummeting. Scientists were culturing microbes with antibiotic activity, but kept isolating the same antibiotics over and over (and over) again. It seems all the low hanging fruit had been picked, and we were out of luck. The low-hanging-fruit problem led to an arduous innovation gap that last over three decades (~1965 – 2000).

Modern Approaches

Antibiotic resistance had been reported for virtually all known antibiotics. Something had to change, so scientists went back to the drawing board.

Scientists used two primary tools to circumvent these problems:
(1) Medicinal chemistry and chemical synthesis – in this approach, scientists used the basic molecular structure of known antibiotics and embellished them. Acting like a Trojan horse, the small chemical moieties appended to the existing structure prevented the bacteria’s resistance machinery from recognizing and neutralizing the antibiotic.
(2) Computing enabled the used of bioinformatics to look at DNA sequences and identify groups of genes (called gene clusters) that were probably involved in producing antibiotics. Using an approach called heterologous expression, these gene clusters could then be moved into microbes we’re able to easily culture, and coax them into producing the antibiotic.
(Bonus) Advances in DNA sequencing powered the use of bioinformatics to look at microbial genomes (called genome mining).

Together, these approaches led to the discovery of a few more important antibiotics (e.g. daptomycin and tigecycline). Many of these antibiotics are now used as last resort antibiotics. Unfortunately, we’re not out of the weeds yet.

Outlook

Antibiotic resistance is a growing problem. The Centers for Disease Control and Prevention (CDC) periodically releases scary graphics like the one below that we mustn’t ignore.

Here’s how you can do your part:
(1) Do not ask for (or accept) antibiotics for common ailments like colds and coughs. Your immune system is strong and capable.
(2) Get vaccinated! If you can’t get sick from certain bugs, you won’t need treatment. (For more, see my blog post on vaccines)
(3) Do not flush antibiotics down the toilet. Throw them in the trash instead. Bacteria in the sewage system will recognize the antibiotic and, sure enough, develop resistance over time. In fact, don’t flush any medicines down the toilet. They can be very hard to remove from water, and end up polluting the environment.

I hope this journey from Fleming’s disorganized bench and serendipitous discovery to the growing concern over antibiotic resistance was informative. I’ll leave you with this:
If today was your first day on earth, bacteria would be 500 years old. Bacteria have a level of collective wisdom that we can’t comprehend, but we can at least try to appreciate.

Have questions or want to add to the discussion? Leave a comment!