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The evolution of one of the greatest medical discoveries in history.

The Path of Least Resistance: Our Relationship with Antibiotics

They think they can beat us with their antibiotics?! Silly humans...

Several weeks ago, while scrolling through your social media feed(s) you may have come across a video depicting Bacteria making their way through increasing concentrations of antibiotics in a large rectangular petri dish. If you have not seen it, need a refresher, or just thought it was cool and want to watch it again, check it out here. The history of antibiotics leading up to this fun video is almost as interesting as what’s actually happening in that petri dish. And as for humanity’s relationship with antibiotics? Well, it’s just a little more complicated.

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Figure 1 Sir Alexander Fleming at work, likely picking up a bacterial colony from a petri dish (Source)

Our story begins with the bacteriologist and physician Sir Alexander Fleming. In his lab, Fleming studied the bacterial genus Staphylococci, which is known to cause boils and sore throats, and lives on healthy skin. Specifically, Fleming was interested in antiseptics that could kill this bacterium, as during his military medical service in world war I he witnessed many soldier deaths due to infected wounds.

This is where the story gets interesting: Rumor has it that Fleming was not the tidiest of people, and when he went on vacation in September 1928, he happened to leave a pile of petri dishes with growing Staphylococci colonies on a lab bench. After several weeks away, Fleming came back to his lab and observed the Staphylococci plates. To his annoyance he found that one of the plates was moldy - There goes that experiment! But wait, it looks like where the mold grew, the bacteria was unable to survive, forming a clearing around the mold. Could it be that the mold is producing some kind of compound to inhibit the bacterial growth? Precisely! Fleming began investigating this new “mold juice” (his term, not mine) produced by the fungus and discovered that the mold that had grown on the plate was of the genus Penicillium (Penicillium notatum), and so he named the magical juice “penicillin”. He began conducting experiments and spreading the word of this newly discovered compound [1,2,3].

Fig 2.

Figure 2 Zones of clearing around antibiotic discs indicate antibiotic susceptibility, while growth near the discs (as seen around the two bottom discs on the right hand plate) indicate resistance. (source: Wikipedia)

Few discoveries in history have had as much of an impact and have saved as many lives as antibiotics. Many diseases that were once considered a death sentence were now curable: Scarlet fever, pneumonia, bacterial meningitis, gonorrhea. Penicillin could even prevent death due to infected surgical and battle wounds [3]. Fleming’s discovery brought us into a new age of medicine. Although the discovery itself was positive, no one could have foreseen the catastrophic consequences associated with the overuse of antibiotics. Soon after the discovery, doctors began enthusiastically prescribing penicillin as the miraculous drug that it is. Other antibiotics were also being discovered and received similar fame and usage. A highly effective drug curing lots of people - what’s the catch, you ask? The problem with this practice has to do with mutations, which are random changes in DNA. Mutations can have no effect at all, they can have negative effects such as disease, or sometimes they can grant their owners a survival advantage. In this case, we are talking about a beneficial mutation (benefits for the bacterium) that enables resistance to a specific antibiotic. Any cell that does not have the mutation dies, and the cells that have the mutation are able to multiply, creating armies of resistant cells. As bacteria began developing antibiotic resistance, researchers uncovered more and more effective compounds to circumvent this problem. But alas, antibiotic compounds are a finite resource, and it seems that we have reached the bottom of the well with a whole lot of resistant strains and no new antibiotics in our arsenal.

Another major change that occurred since this discovery, was the rise of animal agriculture for the purpose of food production. This development resulted in keeping large numbers of animals in environments where bacterial infections thrive. Since a sick animal is not financially beneficial, livestock was now also being treated with high amounts of antibiotics on a regular basis. After ingestion, the antibiotics makes their way into soil and water where additional bacteria will be exposed, giving rise to more resistant mutants. As mutations of antibiotic resistance continue to accumulate, we see a rise in bacterial diseases caused by superbugs – a cool name for bacteria that when treated with antibiotics, continue about their disease causing business completely unharmed. MRSA, tuberculosis, and Clostridium difficile are only a handful of examples of infections that are becoming difficult if not impossible to treat.

So what was so special about that video? It shows a huge tub (120 x 60 cm – about the size of a coffee table) of growth medium with a gradient of two antibiotics: trimethoprim and ciprofloxacin. The gradient goes from no antibiotics to 3000 times the MIC (Minimum Inhibitory Concentration), which is defined as the concentration of a specific antibiotic at which wildtype cells of a bacterial species cannot grow. The researchers showed that when bacteria were directly introduced to the high concentration, they were not able to survive. But when introduced to a gradually increasing concentration, they developed resistance like champs. It also gave researchers a chance to visually and spatially observe the evolution of antibiotic resistance, teaching us about the dynamics of new mutant lineages as they advance to new horizons of antibiotic concentrations that their ancestors could not dream of overcoming [4].

Antibiotics are truly an incredible tool, but as you now understand, prescribing antibiotics is not an act that should be taken lightly. Doctors are aware of this acute problem, therefore if a doctor has gone as far as to prescribe antibiotics, you should follow those instructions and be sure to finish them. For now, hopefully the medical crisis caused by antibiotic overuse can be a lesson to us all, that with great power comes great responsibility.

Oh, and one more moral of the story: Next time your boss/parents give you a hard time about how messy you are, feel free to tell them that sometimes being messy ends up with saving millions of lives, revolutionizing the world of medicine and receiving a Nobel prize!

References:

[1] http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-bio.html

[2] https://www.chemheritage.org/historical-profile/alexander-fleming

[3] https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html

[4] Baym, Michael, Tami D. Lieberman, Eric D. Kelsic, Remy Chait, Rotem Gross, Idan Yelin, and Roy Kishony. “Spatiotemporal microbial evolution on antibiotic landscapes.” Science 353, no. 6304 (2016): 1147-1151.

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