How we reached current resistance

So let’s have a look at a brief history of antibiotics and how we’ve got to our current situation. The antibiotic era is seven decades old. So are we really approaching the post-antibiotic era? Have we abused this precious resource so badly that we soon won’t have these most valuable of drugs? Will what are now considered to be trivial infections once again become killers? Have we come a full circle back to before penicillin became available to use in the 1940s? As things stand, and unless we take urgent action, the answer to all of these questions is yes, there are strains of bacteria out there that are resistant to just about every antibiotic that we’ve discovered so far.

And the discovery of new antibiotics is now much harder than it was. And there are fewer pharmaceutical companies trying.

Can antibiotics be saved? Like endangered animal and plant species, they need our protection. With concerted efforts across international boundaries and with positive engagement from all parts of society, we could pull ourselves back from the edge of the precipice that threatens modern medicine.

The earth is approximately 4.5 billion years old.

The first bacteria probably came into existence about a billion years after that, so perhaps 3.5 billion years ago.

At some point, probably over a billion years ago, some bacteria evolved with the ability to produce chemicals that could kill or inhibit the growth of other bacteria that were competing for essential nutrients or other growth factors. These were the first antibiotic. If you think about it though, antibiotic resistance must have evolved at the same time. After all, any bacteria producing an antibiotic would have had to overcome the effects of whatever toxic molecules they were producing in order to be able to survive. After all, if they hadn’t, antibiotic production would have been an extremely short-lived evolutionary experiment. So right from the start resistance to antibiotics was an entirely natural phenomenon.

Now, travelling forward from that point in time, we have the beginning of eukaryotic life, the development of multicellular organisms, invertebrates, vertebrates, the dinosaurs, numerous cycles of global warming and ice ages, the emergence of mammals, the ascent of man, and the rise and fall of human empires.

And we get to 1859 when Charles Darwin published the first edition of his book, On the Origin of Species. Had he known about bacteria, antibiotics, and resistance, he would doubtless have used them as a perfect illustration of the principles of the evolution and natural selection.

It was Paul Ehrlich who came up with the concept of antimicrobial chemotherapy. He envisaged chemicals that could act as magic bullets by killing the microbes responsible for infections, but without harming the infected patient. His pioneering work with Sahachiro Hata led to the discovery of Salvarsan or Arsphenamine, an arsenic-derived molecule, which was first marketed in 1910 and replaced the older mercury-based drugs for the treatment of syphilis.

Although Salvarsan was the first modern antimicrobial agent, it was not a true antibiotic. Now, strictly speaking, these must be produced naturally by microorganism. The era of true antibiotic stormed in 1928 when Alexander Fleming discovered penicillin in St. Mary’s Hospital in Paddington, England and when clinical use of the agent was started during the Second World War. The success of penicillin led to a search for other antibacterial molecules and heralded a golden age of antibiotic discovery, which continued from the 1940s through to the 1970s. Suddenly, bacterial infections could be treated reliably. And this changed the medical and public expectations and revolutionised the practise of medicine.

Many of the complex surgical and therapeutic procedures we now take for granted were only made possible because antibiotics were available to prevent infections from happening or could treat them effectively if they did happen.

So what went wrong? It doesn’t really matter whether it’s at a microbe level in the environment or in the vast scales that we’ve used antibiotics over the last 70 years or so. Any antibiotic use, even appropriate use, will select for resistance. As we’ve heard, this is an entirely natural response by bacteria. Let’s have a look at a simple example. The bacterial cell is dividing every 20 minutes.

As we can see here, after just two hours, that single bacterial cell is now 64 bacterial cells.

Here, we see a mutant bacterial cell has evolved.

Here, we see how the mutant red bacterial cell has survived despite the antibiotic, represented by the green background. This has killed all of the blue bacterial cells. Any mutant bacteria that are able to grow in the presence of the inhibitory antibiotic molecules– that is the resistant ones– will have a survival advantage over bacteria that are sensitive or susceptible to the antibiotic in the presence of the antibiotic. And so the resistant bacterias multiply, while the others either stop growing or are killed. The resistant ones can then pass on their DNA to their progeny. And resistance is inherited and retained as an advantageous trait.

And as you can see, the resistant bacteria is starting to divide just as the sensitive one did, although this time, in the presence of the antibiotic.

And eventually, or in this case, after only 8 hours and 20 minutes, the environment is overwhelmed by the resistant organism. As early as 1940, before penicillin was being widely used, Edward Abraham and Ernst Chain discovered a penicillin-resistant strain of E. coli. Alexander Fleming described the threat that resistance could pose to the clinical use of antibiotics in his 1945 Nobel Prize acceptance speech. And with that, we have set the scene for the next 70 years, which has been a repeating cycle of antibiotic discovery, often to overcome the previous resistance problem. The introduction of the new drug into clinical use, usually hailed as the latest wonder drug, only to be followed by the gradual erosion of their clinical usefulness because of resistance.

Of course this is a gross oversimplification. Not all bacteria have become resistant to all antibiotics. But no antibiotic has zero resistance. Resistance is an evolutionary inevitability and follows exposure of bacteria to any antibiotic. Although the speed of that resistance emerging varies as also does the extent to which the resistant bacteria and the resistance genes subsequently spread to become a clinical problem. It’s a sobering fact that strains of almost every clinically relevant bacterial species have developed resistance to at least one antibiotic class and have so ended it ineffective as a treatment choice. When we started to use antibiotics in the 1940s, we picked a fight with evolution. And that’s a fight we probably can’t win.

After all, bacteria have been overcoming adverse conditions for billions of years. It’s what they do.