User:Lawler.70/sandbox

Research Question How does antibiotic resistance in bacteria develop and evolve (especially in E. coli)? How can this evolution be slowed and/or prevented entirely? Works Cited Adam, Mike, Bhuvana Murali, Nicole O. Glenn, and S. Steven Potter. "Epigenetic Inheritance Based Evolution of Antibiotic Resistance in Bacteria." BMC    Evolutionary Biology 8.1 (2008): 52. Web.

In this paper, the test subject was antibiotic resistant E. coli. This E.coli was studied using three antibiotics: ampicillin, tetracycline, and nalidixic acid. It may have been more effective to use a greater variety of antibiotics for the study; however, successive exposures to these drugs resulted in greater and greater resistance among the bacteria. This was expected; however, more than 50% of these bacteria reverted back to their antibiotic sensitive state which was indicative of epigenetic inheritance. Looking at antibiotic resistance from an epigenetics standpoint will give my research a fresh angle on the resistance problem.

Andersson, Dan I., and Diarmaid Hughes. "Persistence of Antibiotic Resistance in Bacterial Populations." FEMS Microbiology Reviews 35.5 (2011): 901-11. Web.

First and foremost, this article blatantly states the cause of this resistance epidemic. For several decades, antibiotics have been used excessively even when they are not needed. For example, physicians often prescribe antibiotics as a first resort, and often, these antibiotics are not effective in treating the illness. The author looks at this as well as the overuse of broad spectrum antibiotics. Both of these are key factors in the evolution of antibiotic resistance. The authors also address the clinical effects of resistance and its birthplace in hospitals. My question is this: are you really more likely to pick up an antibiotic resistant bacterial infection inside of a hospital? That seems a bit counterintuitive. Hospitals are supposed to be extremely clean.

Baquero, F., C. Alvarez-Ortega, and J. L. Martinez. "Ecology and Evolution of Antibiotic Resistance." Environmental Microbiology Reports 1.6 (2009): 469-76. Web.

This article is similar to the Andersson & Hughes article, but it has a little more depth. I really like that the author of this paper considers antibiotic resistance to be a direct result of strong selective pressure against antibiotic sensitivity. It makes perfect sense. If you are antibiotic sensitive, you can’t thrive like you could if you were resistant. Something I wish these authors would have addressed a little better was the speed at which these adaptations become measurable. Essentially, I would like to look at how many exposures to an antibiotic it takes to generate a bacterial population with even partial resistance.

Courvalin, P. "Predictable and Unpredictable Evolution of Antibiotic Resistance." Journal of Internal Medicine 264.1 (2008): 4-16. Web.

This paper was fascinating mainly because the author does not believe that eradication of bacterial antibiotic resistance is possible. He believes that our only hope is to slow its evolution a bit. What does he propose we do to slow its onward march? This author also discusses the prominence of antibiotic resistance in the healthcare setting. Bacterial colonies in such a setting are exposed to so many antibiotics that it’s hard not to develop any resistance. According to the author the main reason for this is because antibiotic resistance makes the bacterium more fit. This increased fitness increases the chances of reproduction. Bacteria reproduce very quickly via binary fission; therefore, once established, antibiotic resistant bacteria can multiply exponentially.

Zhang, Quan-Guo, and Angus Buckling. "Phages Limit the Evolution of Bacterial Antibiotic Resistance in Experimental Microcosms." Evolutionary Applications (2012): No. Web.

It’s interesting that the authors refer to antibiotic resistance as a public health crisis; yet, it gets very little media attention. That is until a serious outbreak occurs and fatalities result. People aren’t really aware of the seriousness of the problem, nor the speed with which these bacteria evolve. These authors actually studied the effects of adding a phage to the experiment. They used Pseudomonas fluorescens and kanamycin to study bacterial survival during treatment. They found that the presence of the phage actually decreased the chances that the bacteria would survive and develop resistance to kanamycin. This leads me to believe that the introduction of lytic bacteriophages could be used as a potential prevention technique for antibiotic resistance. I would really like to find a second article addressing the prevention of resistance evolution.

Suggestions and Edits Oct.1
URL  https://en.wikipedia.org/wiki/Antibiotic_resistance

Suggestions in Salmonella and E.coli
Under the sub-heading “Salmonella and E. coli”, it says that “some strains of E.coli have become resistant to multiple types of fluoroquinolone antibiotics.” It might be worth mentioning which strains have developed resistance and what conditions fluoroquinolone antibiotics are used to treat.

Under same sub-heading, the scope of the information on antibiotic resistance in E.coli is extremely narrow. It would be a good idea to expand the article with some general information about resistance in E.coli such as how and when this resistance evolved. Also, it would be beneficial to list a few of the more common antibiotic resistant strains.

Again under this sub-heading, it would be helpful to mention some of the environments (such as hospitals) that resistant E.coli are prevalent.

Edit under Salmonella and E.coli
Both of these bacteria are well known for causing nosocomial (hospital-linked) infections, and often, these strains found in hospitals are antibiotic resistant due to adaptations to wide spread antibiotic use.

FINAL EDITS
URL  https://en.wikipedia.org/wiki/Antibiotic_resistance

Under Prevention: Decreasing antibiotic use
Excessive antibiotic use has become one of the top contributors to the development of antibiotic resistance. Since the beginning of the antibiotic era, antibiotics have been used to treat a wide range of disease and illness. Overuse of antibiotics has become the primary cause rising levels of antibiotic resistance. The main problem is that doctors are willing to prescribe antibiotics to ill-informed patients who believe that antibiotics can cure nearly all illnesses, including viral infections like the common cold. In fact, in a recent analysis of drug prescriptions, it was found that 35.7% of patients with a cold or an upper respiratory infection (both viral in origin) were given prescriptions for antibiotics. These prescriptions accomplished nothing other than increase the risk for further evolution of antibiotic resistant bacteria.

Under Salmonella and E.coli
Although mutation alone plays a huge role in the development of antibiotic resistance, there was a study done recently that found that high survival rates after exposure to antibiotics could not be accounted for by mutation alone. This study focused specifically on Escherichia coli’s development of resistance to three antibiotic drugs: ampicillin, tetracycline, and nalidixic acid. At the conclusion of the study, these researchers found that some antibiotic resistance in E. coli developed due to epigenetic inheritance rather than by direct inheritance of a mutated gene. This was further supported by their data showing that reversion back to antibiotic sensitivity was relatively common as well. This could only be explained by epigenetics. Epigenetics is a type of inheritance where gene expression is altered rather than the genetic code itself. There are many modes by which this alteration of gene expression can occur. This includes methylation of DNA and histone modification; however, the important idea is that both inheritance of random mutations and epigenetic markers can result in the expression of antibiotic resistance genes.

FINAL PAPER
Evolution of Antibiotic Resistance in Escherichia coli and other bacteria

Long before the human race evolved, bacteria were one of the most prominent life forms on this planet. These bacteria have had an extended period of time to evolve in their respective environments, and as a result, they are very well-adapted to thrive in these environments. If this is the case, and bacteria are so well-adapted to their environment, how did antibiotic resistance arise in the first place, particularly in Escherichia coli? Also, now that it is a common concern in modern medicine, how can researchers hope to slow its evolution or even prevent it entirely? In order to answer these questions, one must first look back at the history of antibiotic resistance.

Antibiotic resistance originally began to develop shortly after the introduction of antibiotics around 65 years ago (Baquero et al. 2009). From that moment on, bacterial species, such as E. coli, have been locked in an evolutionary arms race as they coevolve with modern medicine. Both must constantly evolve to outpace the evolution of the other in order to maintain its fitness, and although antibiotics are not technically organisms with which bacteria can coevolve, they are still a dynamic class of drugs that must be adapted to compete with the bacterial infections that they treat. This coevolutionary battle demonstrates what evolutionary biologists refer to as the Red Queen Hypothesis which was established by Leigh Van Valen in 1973 (Hoffman 1991). Essentially, this hypothesis states that in order to maintain the same level of fitness in its environment, a population must evolve fast enough to compete with other rapidly evolving populations (Hoffman 1991). In simpler terms, any given population must be continuously moving at a fast pace in order to remain in the same place relative to another population.

Now, the mechanisms by which these bacterial populations develop resistance are relatively straight forward. Any biology course that covers basic evolutionary concepts will address the majority of the related concepts. First, in order for antibiotic resistance to develop, mutations must arise that either increase or decrease an individual’s overall fitness. In the case of antibiotic resistance, the mutation granting resistance increases an individual organism’s fitness. Because of this fitness differential, there is selective pressure against the bacteria that lack this new mutation. In this case, the process of natural selection will ensure that this mutation becomes more and more common in the population (Baquero et al. 2009). This all makes perfect sense; however, mutations are very rare. If these mutations occur only once every 107 nucleotides (Courvalin 2008), it seems far-fetched that an organism could rapidly evolve through the proliferation of randomly mutated alleles, but that’s exactly how the majority of antibiotic resistance arises. This is due to the rapid proliferation of bacteria during an infection. The large number of rapidly reproducing bacteria in a bacterial infection overcomes the rarity of mutations (Courvalin 2008). Although mutation alone plays a huge role in the development of antibiotic resistance, there was a study done recently that found that high survival rates after exposure to antibiotics could not be accounted for by mutation alone (Adam et al. 2008). This study focused specifically on Escherichia coli’s development of resistance to three antibiotic drugs: ampicillin, tetracycline, and nalidixic acid. At the conclusion of the study, these researchers found that some antibiotic resistance in E. coli developed due to epigenetic inheritance rather than by direct inheritance of a mutated gene. This was further supported by their data showing that reversion back to antibiotic sensitivity was relatively common as well. This could only be explained by epigenetics (Adam et al. 2008). Epigenetics is a type of inheritance where gene expression is altered rather than the genetic code itself. There are many modes by which this alteration of gene expression can occur. This includes methylation of DNA and histone modification; however, the important idea is that both inheritance of random mutations and epigenetic markers can result in the expression of antibiotic resistance genes (Adam et al. 2008).

As mentioned previously, mutation and epigenetics can set the stage for evolution by providing a genotypic basis for the phenotypic variance upon which selection can operate. The next question is this: what provides this selective pressure that drives the evolution of bacterial populations? The obvious answer is excessive antibiotic use. Since the beginning of the antibiotic era, antibiotics have been used to treat a wide range of illnesses (Andersson and Hughes 2011). Overuse of antibiotics has become the primary cause rising levels of antibiotic resistance. The main problem is that doctors are willing to prescribe antibiotics to ill-informed patients who believe that antibiotics can cure nearly all illnesses, including viral infections like the common cold. In fact, in a recent analysis of drug prescriptions, it was found that 35.7% of patients with a cold or an upper respiratory infection (both viral in origin) were given prescriptions for antibiotics (Gilberg et al. 2003). These prescriptions accomplished nothing other than increase the risk for further evolution of antibiotic resistant bacteria.

In addition to over-prescription of antibiotics, there are a couple of other factors that increase the prevalence of antibiotic resistance. One of these factors is the extensive use of broad spectrum antibiotics instead of target-specific drugs. Use of broad spectrum antibiotics, while effective in some cases, often just exposes many different bacterial populations to non-specific antibiotics, providing a selective pressure to drive the evolution of antibiotic resistance (Solomon et al. 2001). The other factors are both based on dosage. If the dosage is suboptimal (enough to control the infection but not enough to kill the bacteria), this exposure to the antibiotic gives these bacteria the opportunity to develop resistance. Then, next time they are faced with the same antibiotic, the drug will prove to be less effective (Andersson and Hughes 2011). Another common problem that contributes to resistance is the failure of patients to finish their entire cycle of antibiotics. Instead of finishing the full dosage, patients often stop taking their medications as soon as their obvious symptoms disappear (Ansersson and Hughes 2011). This provides the perfect environment for bacteria to develop resistance. For example, suppose a patient in the local hospital picked up a nosocomial urinary tract infection caused by E. coli. This patient is prescribed a moderate dosage of ampicillin and instructed to take the medication every day until it’s gone. The patient begins her treatment and on the fourth day, she decides she no longer needs the medication because her symptoms are no longer present. She has just set the stage for the rapid evolution of ampicillin resistance in that E. coli population.

Today, researchers are constantly working to slow this rapid evolution with new treatment methods. These methods (which are not limited to use against resistant E. coli) include, but are not limited to: drug overkill, exposure to lytic phages and antibiotics, rotation of drug treatments, limiting exposure of bacteria to the most powerful drugs, and avoiding the use of broad-spectrum antibiotics (Palumbi 2001; Zhang and Buckling 2012). Drug overkill is a method that inhibits the evolution of antibiotic resistance by ensuring that all of the bacteria in an infection are eliminated. This is typically done with a combination of several antibiotics (Palumbi 2001). By killing all of the involved bacteria, this method leaves no bacterial population on which selective pressures can act, so evolution cannot occur in that specific population (Palumbi 2001). An example of the drug overkill method when dealing with a severe E. coli infection might entail treatment with ampicillin, tetracycline, and nalidixic acid (Adam et al. 2008). Instead of using just one of these drugs, all three are used simultaneously to ensure complete eradication of the infection.

Another approach to slowing the evolution of antibiotic resistance is the use of lytic phages in conjunction with an antibiotic to decrease bacterial survival and evolution (Zhang and Buckling 2012). In a recent study, researchers found that when Pseudomonas fluorescens bacteria were treated with both a lytic phage and kanamycin, evolution of antibiotic resistance was nearly halted (Zhang and Buckling 2012). Neither of these treatments was sufficient on its own. When treated with just the phage, all twenty-four P. fluorescens survived and evolved resistance to the phage. When treated with kanamycin, twelve of the twenty-four populations survived, but together they were able to kill all but one of the twenty-four P. fluorescens populations used in the experiment (Zhang and Buckling 2012). This could become a fairly useful approach as it has only recently been introduced. Other common methods used to slow the evolution of antibiotic resistance are limiting the exposure of bacteria to the most powerful drugs, rotation of drug treatments, and avoiding the use of broad-spectrum antibiotics (Palumbi 2001). Limiting exposure to powerful drugs, such as vancomycin, is beneficial because less exposure means fewer opportunities for bacteria to develop resistance. As a result these powerful antibiotics are effective longer and are often used a last resort when other treatments fail (Palumbi 2001). Another conceptually similar method is the rotation of drug treatments. By cyclically alternating the antibiotic treatments used, exposure to one specific drug is limited, and again, that means fewer chances for resistance to develop (Palumbi 2001). Limiting the use of broad-spectrum antibiotics is also based on the same principle. Limiting exposure to the same antibiotics definitely helps to slow the evolution of resistance (Palumbi 2001).

Antibiotic resistance is major public health concern today; however, most people do not realize the seriousness of the situation. It’s actually rather difficult to comprehend just how quickly these bacteria are evolving to compete with modern medicine. As demonstrated by E. coli, resistance arises when a natural selection acts on a trait demonstrating phenotypic variance. This variance is the result of a random mutation that confers a fitness advantage in an environment containing antibiotics (Baquero et al. 2009). This evolutionary process is inevitable and complete eradication of resistance is highly unlikely, if not impossible. However, it can be slowed via the methods mentioned above (Courvalin 2008; Palumbi 2001), and although these methods have proven effective in controlling the rapid evolution of resistance, the evolutionary arms race will continue. Bacteria will continue to evolve in response to the evolution of antibiotic drugs, and in turn, antibiotic drugs will continue to evolve in response to the evolution of bacterial resistance (Hoffman 1991). It’s an endless cycle, and as a result, antibiotic resistance will likely be a major research topic for years to come.