How do Bacteria Develop Antibiotic Resistance?

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…

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4 Responses to “How do Bacteria Develop Antibiotic Resistance?”

  1. Jake Bonn says:

    Random mutation and utter negligence are to blame for the rampant spread of MRSA.
    Hospitals continue to allow their staff to leave the confines of the hospitals and go directly out into public places without decontaminating and still wearing their “scrubs”. They touch produce in the grocery stores,they drive kids to soccer and school and always make sure to cross contaminate every surface or individual they come into contact with en-route to and from work.After tattooing professionally for 30 years I have learned a few things about cross contamination prevention,blood-borne pathogens and Staph Infections.I have never infected anyone with anything, and I educate my colleagues and peers to the best of my ability at every opportunity. The medical associations do not ever publish the fact that over 400,000 nurses and doctors are indeed “Carriers” of MRSA and are continued to be allowed to continue working in the health care industry.The conduct of physicians and nurses working under corporate governance is deplorable.

  2. Barbara Cowley says:

    Excellent article.I survived MRSA bilateral pneumonia with abscess to both lungs which I aquired working as an L.P.N.,Pt.Porter in our local Hospital.Ironically,I was a huge opponent of private companies taking over services,especially Housekeeping. However,Thanks to a Team of Specialists and awesome Nurses and support staff, along with the right combination of drugs,I survived.(I also had a very strong will to fight this life threating bacteria…..Thanks for the article and for letting me share my story………B.Cowley

  3. J. Wild says:

    We have a 12 yr old family friend who has gone through countless tests and surgeries and has been on and off IV antibiotics now since early summer 2011. The antibiotics are not working for the infection hiding in her ankle region. Is there even an alternate path to be taken at this point?! If there is, what could the drs now focus as a new direction of attack? Just frustrated and thinking out loud…

  4. Norman Silva says:

    Superbugs not super after all
    by Carl Wieland
    After over 12 years as a medical practitioner, I suddenly found myself an avid consumer, rather than a provider, of medical care. Involved in a serious road accident in 1986, I spent many months in hospital, including weeks in an intensive care unit.
    While in intensive care, I became infected with one of the varieties of so-called ‘supergerms’, which are the scourge of modern hospitals. These are strains of bacteria which are resistant to almost every (and in some cases every) type of antibiotic known to man.
    Several others in the same unit with me died as a result of infection by the same bacterial strain. The germs overwhelmed their immune systems and invaded their bloodstream, untouched by the most expensive and sophisticated antibiotics available.
    This ‘supergerm’ problem1 is an increasingly serious concern in Western countries. It strikes precisely those hospitals which are more ‘high-tech’, and handle more serious illnesses. Applying more disinfectant is not the answer; some strains of germs have actually been found thriving in bottles of hospital disinfectant! The more antibacterial chemical ‘weapons’ are being used, the more bacteria are becoming resistant to them.
    Natural selection, but not evolution
    Evolution is basically the belief that everything has made itself—that natural processes (over millions of years, without miraculous, divine input of intelligence) have created an increasingly complex array of creatures. According to evolution, there was once a time when none of the creatures in the world had lungs. This means that there was no genetic information (the ‘blueprint’ for living things, carried on the molecule DNA) for lungs—anywhere. Then, at a later time, ‘lung information’ arose and was added to the world, but no ‘feather information’ as yet—feathers evolved later.
    In other words, for every feature which arises by evolution, there would need to be new genetic information added to the total information in the biosphere (i.e., all the information in all creatures on earth). Some features could be lost subsequently, of course, so there will not always be a gain, but if microbes turned into magpies, maple trees and musicians, there must have been a massive net increase in information. This is not just any jumble of chemical sequences, but meaningful information, since it codes for complex structures which have purposeful functions.
    So if new information, new functional complexity, can be shown to be arising by itself where previously there was none, this would give some credibility to the idea of molecules-to-man evolution, although it would not strictly prove that it had occurred. However, it can be shown that in every situation where populations of living things change, they do so without increase (and often with a decrease) of information. Thus, it is completely illegitimate for anyone to claim that such changes show ‘evolution happening’. Let’s look at what is known about how the ‘superbugs’ became resistant, and ask—did any new structures or functions arise in the process (which is another way of asking whether there was any evidence of evolution)?
    There are a number of different ways in which germs can become resistant to these poisons. A ‘superbug’ is, by definition, resistant to many different antibiotics. It may have become resistant to antibiotic A in one way, to antibiotic B in a completely different way, and to antibiotic C in another way again. So if we look at all the known ways of resistance arising in a population of germs, we will see if any of them are uphill, information-adding processes.
    1. Some germs already had the resistance.
    If out of a million bacteria, five already have a feature which makes them resistant (however that arose) to, say, penicillin, then soaking them in penicillin will kill all of them except for the five. Now the body’s natural defenses will often ‘mop up’ such a small population before it can multiply and cause harm, so resistance will not become a problem. However, if that doesn’t happen, then those five germs can multiply, and their offspring will obviously also be resistant. So within a short time, there will be millions of germs resistant to penicillin. Notice that:
    (i) This is why multiple resistance to major antibiotics is more common in hospitals which treat more serious conditions—these are the hospitals which will frequently be using the sophisticated, expensive ‘heavy artillery’ antibiotics, so this sort of ‘natural selection’ will happen more often.
    (ii) In this kind of instance, the information to resist the antibiotic was already there in the bacterial population—it did not arise by itself, or in response to the antibiotic. That some germs were already resistant to man-made antibiotics before these were invented is common knowledge to microbiologists. Soil samples from villages where modern antibiotics had never been used show that some of the germs are already resistant to drugs like methicillin which have never existed in nature. Bacteria revived from the frozen intestines of explorers who died in polar expeditions carried resistance to several modern antibiotics, which had not been invented when the explorers died.2
    2. Some germs directly transfer their resistance to others.
    In an amazing process, the closest thing to sex in bacteria, one germ inserts a tiny tube into another, and a little loop of DNA called a ‘plasmid’ transfers from one to another. This sort of gene transfer, which can obviously pass on information for resistance to a drug, can even happen between different species of bacteria.
    Notice, again, that the information for the resistance must already exist in nature before it can be passed on. There is no evidence of anything totally new arising which was not there before. This is information transfer, not information creation.
    So far, we have dealt with situations in which resistance was obviously already there. Evolutionists would claim, of course, that such resistance evolved originally in the (unobservable) past. However, if observed changes in the present do not show us new information, what support is there for the idea that such information arose in the past? The mechanism that is put forward for this past evolution is invariably mutation—a copying mistake, an accidental change in the DNA code passed on to the offspring. So that brings us to the final way in which bacteria can become resistant.
    3. Some germs become resistant through mutation.
    Interestingly, where this happens, there is no clearcut evidence of information arising. All such mutations appear to be losses of information, degenerative changes. For example, loss of a control gene may enhance resistance to penicillin.3
    Some antibiotics need to be taken into the bacterium to do their work. There are sophisticated chemical pumps in bacteria which can actively pump nutrients from the outside through the cell wall into the germ’s interior. Those germs which do this efficiently, when in the presence of one of these antibiotics, will therefore efficiently pump into themselves their own executioner.
    However, what if one of these bacteria inherits a defective gene, by way of a DNA copying mistake (mutation) which will interfere with the efficiency of this chemical pumping mechanism? Although this bacterium will not be as good at surviving in normal circumstances, this defect actually gives it a survival advantage in the presence of the man-made poison.4 Once again, we see that information has been lost/corrupted, not gained.
    It is precisely because the mutations which give rise to resistance are in some form or another defects, that so-called supergerms are not really ‘super’ at all—they are actually rather ‘wimpy’ compared to their close cousins. When I was finally discharged from hospital, I still had a strain of supergerm colonizing my body. Nothing had been able to get rid of it, after months in hospital. However, I was told that all I had to do on going home was to ‘get outdoors a lot, occasionally even roll in the dirt, and wait.’ In less than two weeks of this advice, the supergerms were gone. Why? The reason is that supergerms are actually defective in other ways, as explained. Therefore, when they are forced to compete with the ordinary bacteria which normally thrive on our skin, they do not have a chance. They thrive in hospital because all the antibiotics and antiseptics being used there keep wiping out the ordinary bacteria which would normally outcompete, wipe out and otherwise keep in check these ‘superwimps’.5
    If they are ‘weaker’, then why do they cause so much death and misery in hospitals? These bacteria are not more aggressive than their colleagues, it is only that doctors have less power to stop them. Also, those environments which will tend to ‘select’ such resistant germs, like intensive care units, are precisely the places where there will be critically injured people, physically weakened and often with open wounds.
    This is why more than one microbiologist concerned about these super-infections has mused (only partly tongue in cheek) that the best thing to happen in major hospitals might be to dump truckloads of germ-laden dirt into the corridors, rather than keep on applying more and more chemicals in a never-ending ‘arms race’ against the bacteria. In other words, stop using the antibiotics (which of course is hardly feasible), and all this ‘evolution’ will reverse itself, as the bacterial populations shift back again to favour the more hardy, less resistant varieties.
    Summary and Conclusion
    1. ‘Supergerms’ are actually not ‘super’ at all. They are generally less hardy, and less fit to survive outside of the special conditions in hospitals.
    2. There are many instances in which germs become resistant by simple selection of resistance which already existed (including that ‘imported’ from other bacteria).
    3. Where a mutational defect causes resistance, the survival advantage is almost always caused by a loss of information. In no case is there any evidence of an information-adding, ‘uphill’ change.
    4. ‘Supergerms’ give no evidence to sustain the claim that living things evolved from simple to complex, by adding information progressively over millions of years.

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