At the very heart of the growing MRSA crisis in North America is the concept of bacterial resistance to antibiotic therapies. MRSA has found its way into the popular media, and people are becoming accustomed to reading stories about bacterial infections that can’t be treated with standard antibiotics. These stories, however, often gloss over or completely skip one important part – how did these bacteria become impervious to our best medicines in the first place? I’m not talking now about why or how antibiotic overuse and improper use has increased the number of resistant bacterial strains in recent years. Not that that isn’t important, but it’s something I’ve addressed in previous posts. No, I’m talking about how, down at the nitty-grittiest level, one little bacterial cell decides one day that it will no longer be affected by the very poison that was designed specifically to kill it?
I’m going to try not to get too technical in discussing a subject that is inherently technical and scientific in nature. Many clinicians and researchers dedicate entire careers to studying mechanisms of antibiotic resistance, and the detail of understanding now goes right down to the molecular level. Firstly, it must be understood that in many ways a bacterial cell looks and works differently than a cell from our bodies. Bacteria still have a genetic code contained within DNA, but in bacteria some of this DNA floats freely inside the cell, often in circular structures called plasmids. The interesting thing about bacteria is that they can pass plasmids (and thus, genetic code information) amongst each other through a process called plasmid transfer. This process allows certain traits that a single bacterial cell might possess to be shared with nearby bacteria quickly. A second key difference is that a single bacterium can divide into two new cells on its own, without the need for sexual reproduction between two parent cells.
But now I’m already getting ahead of myself. The original question was not how bacteria transfer resistance, but how they develop it in the first place. Bacteria use chemical-based processes to live, grow, and replicate just like we do. At the heart of these processes are protein molecules. Proteins perform a range of specific functions, from destroying/changing other molecules, to forming physical structures and barriers, to helping build new molecules by joining other smaller molecules together. In fact, proteins are so integral to life as a bacteria knows it that just interfering with the creation or function of one key protein can mean sure death. This is the concept that most antibiotics are designed on. The original prototype antibiotic, penicillin, for example works by interfering with a specific protein that helps bacteria to build a strong cell wall.
When a living cell replicates its genetic code in preparation for division, there is the possibility of mistakes occurring that will lead to the formation of abnormal proteins. These mistakes are called mutations, and in humans mutations are the basis for cancers and other diseases as well as the mechanism by which we evolve as a species over time. The same holds true for bacteria, except on a MUCH faster scale. Since bacteria can multiply in hours as opposed to years, genetic mutations are passed on so quickly that an entire population of bacterial cells with the same mutation can be created in the span of a couple days. Sometimes a mutation is immediately lethal to the original bacterium in which it occurs. Other times the mutation results in a protein that is changed just enough to remain functional for survival, but is no longer recognizable as an antibiotic target. When this one in a million event occurs, you now have a bacterial cell that can no longer be killed by antibiotic treatment. This is the basic concept behind why regular Staph infections can be easily treated with a course of antibiotics, while MRSA infections can be life-threatening.
So, through the process of genetic mutations forming proteins that cannot be attacked by antibiotics, a single bacterial cell is able to survive while all others around it are destroyed. There are four primary ways in which this new resistant bacterium will deal with antibiotic treatments, all related to protein changes. It may now be able to produce enzymes (a type of protein molecule) that actually destroy the antibiotic molecule before it has any effect. Alternatively, the actual protein binding site that an antibiotic molecule previously recognized might by changed such that the antibiotic can no longer associate with it. Another possibility is that the bacterium now uses alternate metabolic pathways for survival, abandoning the one that the antibiotic was interfering with. Finally, the bacterial cell may now be able to produce protein channels and pumps in it that help to get rid of antibiotic molecules.
Now we come back to the concepts of DNA, plasmids, and the transfer of resistance. One surviving bacterium on its own with a mutation that gives it resistance to an antibiotic doesn’t sound like much of a problem, does it? However, imagine that this single cell now has all the room and nutrients that it needs to grow and divide, without any competition from its recently deceased brothers. In a matter of hours or days a whole new population of bacteria can be grown from this one parent cell. Because the genetic code is passed on, all of these millions of descendants will have the same mutation that made the original parent resistant to a specific antibiotic. You now have a strain of antibiotic resistant bacteria, and enough of them to potentially cause a serious infection. If this wasn’t bad enough, because bacteria can also transfer plasmid DNA amongst themselves that mutation may also be passed to non-descendant bacteria. This process will also contribute to resistance, and may even allow the creation of totally different resistant strains.
Hopefully this very general explanation will help in the understanding of how a single random genetic mutation can create a worldwide healthcare concern. The key is that bacteria can grow and divide so quickly, achieving in a short time what would take humans a thousand years or more. Future posts will deal with the different subtypes of MRSA, and why part of the fight against this superbug is the effort of constantly changing approaches just to keep up…