So in my previous post I provided a brief overview of antimicrobial resistance, and why the concept merits concern. In this post I will discuss how resistance develops. In most cases, I will be using bacteria as an example of an organism that develops resistance, but the same principles hold true for other pathogens (viruses, protozoa, fungi, and so forth). One thing that I have noticed is that people have a tendency to anthropomorphize a bit when it comes to thinking about pathogens developing resistance. Remember that bacteria are single-celled organisms. Reproduction means that once a bacterium grows large enough, it splits into two virtually identical daughter cells. Under optimal conditions, this can happen in anywhere from four to twenty minutes. Here is a great time-lapse video of E. coli replication, to give you some idea of what we are talking about. In multicellular organisms, cellular reproduction happens in a similar fashion, but growth and reproduction must be coordinated between all of the different cell types, making it a rather more complicated process.
Differences between the “parent cell” and the “daughter cells” are the result of changes (mutations) in the genetic material of the offspring. Understand that this happens all of the time, not just in bacteria, but in viruses, in butterflies, in fruit bats, in you and me and all other living creatures. Small changes in our genetic material, the hereditary blueprints for what we are, happen all of the time. If the mutation interferes with a function necessary for survival, the cell dies. End of story. If the mutation produces no noticeable change, then we call that a “silent mutation”, and the cell carries on as usual. In a multicellular organism like a human, made up of potentially trillions of cells, you are not going to notice when one cell makes a mistake and dies as a result. You will notice, however, if that one cell makes a mistake that results in rapid and abnormal cell growth…we call that cancer. Mutations are not always lethal. If the mutation results in changes that do not kill the cell, but make it less efficient, or somehow weaker, then the mutation puts that cell at a disadvantage relative to others around it. On the other hand, if the mutation provides some benefit to the cell, that puts the cell at an advantage over those around it.
In a human, such changes have little or no effect, unless that cell happens to be a reproductive cell, in which case the change will be passed on to our offspring. In single-celled organisms, however, such a change is very significant. If the mutation makes it weaker, then it will not be able to compete with other cells or organisms and its offspring may die off. If the change makes it stronger, then its offspring will also be stronger and may outcompete the other cells or organisms around it. This process is called natural selection, and it occurs in single-cellular and multicellular organisms alike. The graphic to the left presents a simple model for natural selection using a beetle as an example. In this case, we have green beetles and brown beetles in a population of beetles. At some point in the past, there was a mutation that causes some beetles to be brown in color, rather than the usual green. The birds in this example prefer the green beetles, perhaps because the brown ones blend in better, or perhaps because they resemble something poisonous. Regardless of the reason, since the birds preferentially eat the green beetles, the brown color confers a selective advantage, and they outcompete the green beetles.
Now imagine that, instead of birds and beetles, we have bacteria and antibiotics. Treatment with antibiotics imposes what is known as selection pressure on the bacterial population. If no resistance exists within the population, then all of the bacteria die off. On the other hand, if some mutation results in a bacterium that is resistant to the drug, then that bacterium and all of its offspring are much more likely to survive and become the dominate the population. In the example with the birds and the beetles, we call what happens natural selection. In the case with the bacteria, what we are dealing with is artificial selection, or selective breeding, because humans are imposing these selection conditions upon the bacteria. You have to understand that bacteria are naturally capable of developing resistance to an antibacterial drug. It is entirely possible that it could happen on its own, but unless there is pressure being applied to the population that gives that particular bacterium an advantage over the rest, then it is not necessarily going to take over the population. It will just exist as a part of the population, as in panel one of the graphic above. Applying antibiotics confers selection pressure (panel two), allowing the resistant bacteria to become the dominant member of the population (panels three and four). Understand that I am just giving you the simple version of the story. I have not even addressed the fact that resistance can be shared by gene transfer between organisms.
The thing about bacteria, as opposed to beetles (or any multicellular organism), is that they reproduce really quickly. Remember that a bacteria can divide in as little as four minutes. Think about that. We are talking about a population that can double every four or five minutes (if the conditions are favorable). In the U.S., the average age for a first-time mother is somewhere around 25 years old now. We are talking 25 years before the average human reproduces. I am not even going to do the math to calculate how many generations of bacteria (even at sub-optimal conditions) would take place in 25 years.
The take-home message here is that bacteria evolve much more quickly than we do. When we talk about resistance, we are not talking about one single super-bacteria that lives for years and becomes progressively stronger as it build up immunity to drugs. We are talking about populations that grow and change over time, and the affect that selection pressure has on those populations. We are talking about the fact that humans beings impose selection pressure on these populations, much to our own immediate gain and long-term detriment. In my next post, I intend to discuss how we apply selection pressure through overuse of antibiotics, and some of the issues surrounding this problem.