Monday, April 12, 2010

Resistance to drugs and poisons

Coyne says that "in 1941, [penicillin] could wipe out every strain of staph in the world. Now, seventy years later, more than 95 percent of staph strains are resistant to penicillin" (131). It is very evident that antibiotics are rapidly losing their effectiveness against bacterial infections. Scientists as of now have been able to produce new types of antibiotics that bacteria aren't resistant to, but they are rapidly running out of new kinds. Also, the use of bacteriophages to kill pathogenic bacteria is an area of extensive research to cure infections. What are some ways that scientists are trying to apply the use of bacteriophages to cure sicknesses, and what are other methods which biologists are researching to cure infections? Have there been any recent advances in the treatment of viral infections?


  1. Because of the rapid growth and short generational periods of bacteria, it is very easy for them to develop random changes that result in antibiotic resistance. This phenomenon “comes from evolution of the microbe, not habituation of patients to the drugs” (Coyne 131) and thus is not related to humans becoming more resistant to antibiotics themselves, which is a common misconception. However, there are alternatives to using only antibiotics in order to treat bacterial infections, and it is prudent to explore all of these possibilities because the anti-antibiotic changes occurring in bacteria make the threat ever more great. In layman’s terms, the more we kill the weak bacteria by using antibiotics, the strong bacteria remain and flourish, thus making antibiotics less and less effective. However, there is hope.

    The first alternative to antibiotics is the bacteriophage. Bacteriophages are naturally occurring viruses that target bacteria as their host cells. The phages inject their genetic material into the bacteria, which then hijacks the RNA transcription pathways, and kills the bacteria. Eastern European physicians “have been using phages safely since the 1920s to treat conditions that defy conventional antibiotics, from strep and tuberculosis to infected sores” (Svoboda), and no resistance has been built by the bacteria. Sounds like a miracle cure, no? In many ways, it is. A simple injection of the bacteriophages will kill the specifically targeted foreign bacteria with no problem at all, and no bacteria can resist this means of attack. Currently, the treatment is undergoing FDA approval, and it is a long road. However, it is not a perfect solution. Because the treatment is so specific, it is difficult to pinpoint which bacteriophage one should give in order to treat infection. Also, phages have the ability to mutate into a human-infecting virus, even though the probability is low, yet it is still there. This is not the only solution though…

    Another possible solution is the use of cytokines. Cytokines, as we learned during the immunity unit, are the proteins released by T-cells that initiate a positive feedback cascade, calling more T-cells into action. These types of treatments “are primarily focused on amplification of the host defense system through the administration of cytokines” (Nelson et al). By giving a person cytokines geared towards bacterial infections, for example, one can initiate an immune response towards the bacteria causing the problem and make the body fight even harder. Really, it is not like a foreign substance killing the bacteria like antibiotics do which allows the potential for resistance to grow, but rather initiating the body’s own immune response to do the job. This particular treatment can also work for viral infections, because cytokines are also involved in that pathway as well. Now, it is all up to the FDA and pharmaceutical companies to take this research into practice, and hopefully diminish or even eliminate the use of antibiotics to protect the human race against such harmful evolution of pathogens.

    Page 131 of the book

  2. There is a fundamental flaw with using antibiotics to combat bacterial infections. As shown by the example with penicillin in 1941, at first, antibiotics can kill majority of a species of bacteria. However, the bacteria that the antibiotics does not kill has a naturally acquired immunity to the antibiotic through mutations in its genetic code. The bacteria with this immunity are able to survive and reproduce. Due to the short reproduction cycle of bacteria, as short at replicating every 20 minutes, a bacterial population can rapidly grow back. However, this time when it grows back, since only the antibiotic resistant bacteria can replicate, the whole population of bacteria has this immunity. With a population of bacteria resistant, the drug is no longer useful in killing its target. As people keep creating new drugs to target bacteria, the bacteria's population continues to be wiped out then replenished by resistant survivors. The only way to avoid such a situation would be to ensure that the first wave of the antibiotic makes the species of bacteria extinct. However, this is unrealistic because of both the high mutation rate of bacteria and the large population of bacteria.

    MRSA is a strain of staph that is now highly resistant to antibiotics. Most MRSA infections are in people with weak immune systems. It is most commonly found in places such as hospitals because it can survive in the clean environment. On page 129, Coyne describes an experiment with E. coli in which the bacteria was able to survive in an environment without a gene required to break down a food source. A mutation allowed for the creation of another enzyme which allowed the breakdown of glucose and allowed for the survival of the organism under what was believed to be unsurvivable conditions. This proves how bacteria can have complex adaptations to survive in difficult environments such as sterile hospitals.

    With the discovery of bacteriophages, scientists have a new way of attacking pathogenic bacteria without the high risk of the bacteria becoming resistant like with antibiotics. Bacteriophages are viruses that attack specific bacteria. Since there is a higher mutation rate of these viruses than the bacteria, there is less of a chance that the bacteria is able to acquire a resistance to the virus. Although bacteriophages were discovered around the time of antibiotics, they were not researched deeply because antibiotics were much more general in killing bacteria. Phages are much more specific to the type of bacteria they can kill; this allows them to be more effective in targeting only harmful bacteria and allows scientists to "engineer" specific phages. However, playing with viruses can have its consequences. They are so effective in killing bacteria due to their high mutation rate, but this mutation rate can work against people. Like bacteria, some viruses have become resistant to our antiviral drugs. A common example is how the HIV virus is now immune to AZT (Coyne 131). Therefore, even phages would be working for people, one mutation could cause more damage to humans than the bacteria invader they were trying to fight.

  3. Well Scottie, you may be in luck cause I wrote a JAE on this same topic. Man I miss JAEs...

    As you already mentioned, current antibiotics like penicillin are becoming less and less effective due to our friend evolution. Bacteria are adapting different defenses to combat common antibiotics that only target certain pathways. For example, they have developed less permeable membranes, keeping dangerous antibiotics out of the cell. Another adaptation which decreases the effectivity of antibiotics is the development of an SOS network used to repair damaged DNA. This counters any attempt by antibiotics to damage the DNA of a bacteria (that would result in cell death, but with this new pathway, the DNA is repaired).

    My JAE was done on the effects of COMBINING treatments with certain phages and antibiotics. The organism was E. coli, and this bacteria had an SOS pathway in which it could repair damaged DNA. Commonly, the antibiotic ofloxacin would be used as treatment. This damages the DNA, proteins, and lipids by inducing the formation of radical hydroxyl groups. This used to kill the bacteria, however, it exterted a lot of evolutionary pressure,therefore, the bacteria was able to evolve (in a relatively short time), and survive and reproduce. The purpose of the experiment was to find an effective treatment while simultaneously decreasing the evolutionary pressure put on the organism (therefore, it wouldnt be able to develop resistances). 2 phages were used, one that was lethal to the bacteria, and had relatively high evolutionary pressure; and a phage that attacked the SOS pathway, which, when used with the antibiotic, would kill the cell, and had relatively low evolutionary pressure. The second phage overexpressed certain genes that would keep the old evolutionary resistance from functioning, so ofloxacin could kill the cell. The bacteria would not develop a resistance to the phage because it isn't lethal, but the resistance that kept the antibiotic from functioning was being disabled by the phage, so the bacteria would be left defenseless.

    This is just one example, but it exemplifies certain new treatments that use bacteriophages as "adjuvants" to antibiotics. One big drawback to this treatment though is that a very specific diagnosis is necessary to figure out which phage needs to be used. Phages are very very specific and will not work on any old bacteria.


    Mr. Erdmann
    Jerry Coyne
    L,T., C, J. (2008). Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy. Proceedings of the National Academy of Sciences. 106(12), 4629-4634. (MY JAE)

  4. Bacteria and viruses are the bane of human health. In surviving and reproducing, they hurt our chances of doing the same. Many, if not all human attempts to permanently kill bacteria have been unsuccessful. As you stated Scottie, penicillin could kill all strains of staph 70 years ago, but today is all but completely ineffective. The rate at which bacteria reproduce is to blame for this, compared to mammals, bacteria can divide in as little as 20 minutes (1).
    Bacteriophages are defined as viruses that infect bacteria. In Georgia, and unofficially in other former soviet states, bacteriophage therapy has been used for almost 90 years to target and kill specific bacterial infections. Phage therapy has the benefit of being an alternative to antibiotics, which are slowly failing in power, but on the other hand, the phages can only target specific strains of bacteria. However, only targeting the bad strain of bacteria will prevent the unnecessary killing of useful bacteria (like in the gut). Other potential disadvantages include only being able to use a certain phage once because of the antibodies that are secreted to defend against the phage, it is still a virus, after all.
    Like antibiotics, bacteria can become resistant to treatments, and in this case they can mutate to survive the phage treatment. However, evolution drives the rapid emergence of new phages that can destroy bacteria that have become resistant. This hopefully means that as new bacteria evolve, new phages will evolve to counter those bacteria. (3)
    Another possible way to fight bacterial infections is by tagging bacteria with a molecule, specifically alpha-gal epitope, which is a molecule that humans are highly immune to. Alpha-gal epitope is found in pig heart valves and numerous attempted transplants have shown that our nervous system responds quickly to phagocytize them. This basic idea of this tagging is to “tap into an already established immune response” to the alpha-gal epitope and thus quickly destroy an invader before it can spread. DNA aptamers attach to the a-g epitope, and then the aptamer can be programmed to attach to a certain part on a pathogen. The aptamer will then seek out the pathogen and the body’s normal immune response can effectively kill bacteria which have evolved defenses that prevent normal immune responses from working. This method also happens very quickly and does not need “5-6 days” to develop effector cells to kill the bacteria, which in that time, the bacteria may have already killed its host. (2)
    In laboratory testing on mice, the results were very promising. Mice treated with a drug using the tagging idea helped 100% of the mice survive, while the second closest survival rate was 40% using a different drug type. This could be applied to other bacterial infections like S. Aureus, which is growing incredibly resistant to traditional antibiotics and even multi drug cocktails.