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Quinolone antibiotics have been seen to cause some bacteria to speed up horizontal gene transfer in certain bacteria populations and subsequently the antibiotic resistance process via what is known as an SOS response. "Vibrio cholerae" exhibits this SOS response when exposed to the addition of the drug ciprolaxin, which is a fluoroquinone antibiotic, and speeds up its transfer of genes necessary for resistance. This SOS response has also been able to be prevented in vivo and has been talked about among scientific circles as being one of the most important aspects in trying to combat antibiotic resistance because of the way in which it induces mutations and gene transfer among bacteria populations.

Quinolone antibiotics are a relatively new class of antibiotics that work by interfering with proteins called topoisomerases, which assist DNA replication by loosening tightly wound DNA and making it accessible. In order to do this, the topoisomerase must first break the DNA strands and fill in the gaps with a transient protein bridge. In most cases, the bridge is removed and the DNA is reconnected after the topoisomerase has done its job, but quinolones bind to this protein bridge and prevent the DNA from resealing. The freed double-strand ends signal that DNA damage has occurred and activate the cell's repair pathway. This DNA damage is what then sets off the SOS response. Researchers suggest that these quinolone antibiotics as well as other antibiotics that cause similar kinds of DNA damage may go on to increase the likelihood that bacteria will evolve resistance and that new generations of drugs will have little chance of succeeding where today's drugs have failed. But new research on this subject has seen that by preventing these SOS response genes from becoming activated, mutations and consequently evolution no longer can occur thus allowing possible treatment on this bacteria.

Article link: [ [Antibiotic Resistance] ]

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Antibiotic resistance: solely consequence of evolution via mutation or also caused by selection against certain preexistent resistant genes?

Arguably one of the most pertinent dilemmas in the treatment of infectious diseases and one of the hottest topics in modern science and health today has to do with the growing problem known as antibiotic resistance. Occurring as a result of multiple factors, one of which relates to the improper use of antibiotic drugs used for treatment of certain bacterial illnesses, many organisms today are much harder to treat than they may have been years ago because of resistant genes that may have developed in the organism’s genome. Health professionals and researchers have been working extremely hard as of late to try to solve this phenomenon in order to help prevent a large scale epidemic that could eventually occur if a deadly bacteria were to surface that was resistant to all the drugs that are available for treatment.

While it is generally accepted that this resistance was solely caused by new genes generated through the natural selection of these organisms by inheriting favorable mutations stemming from overexposure to a certain drug, a recent debate has surfaced that may explain this resistance as being caused by environmental selection of genes that are already preexisting forms of a certain resistant gene and not from mutations. While multiple factors go into why antibiotic resistance has become such a problem today, mutation and lateral gene transfer could be the integral components in trying to eventually solve this problem and successfully impede its advancement down the road.

The genetic resistance that has occurred in certain bacteria is, simply put, caused by new genes in its genome and one of the only ways to successfully do this is through mutations. Antibiotic resistance at its core is the developing of new genes by an organism, namely bacteria, that are resistant to a certain drug or therapeutic treatment and consequently become much difficult to treat. Therefore, in order for an organism to change its genome it must somehow get new alleles into its genome. This is where the role of mutations comes into play when discussing antibiotic resistance. These organisms after being exposed over time to a certain treatment do not all become eliminated from a population and survive as a result of antibiotic selective pressure and continue to populate. There must be a reason that these organisms were successfully able to avoid eradication and reason could stem from the organism having a favorable mutation that allowed them to survive and thrive afterwards. Bacteria also have a much more favorable situation for getting new genes as a result of mutations than other organisms. Being single celled, containing a haploid genome, and having short regeneration times, these organisms can thus develop and accrue favorable mutations very quickly in order to affect phenotypic alterations that will aid bacteria in avoiding perishing from whatever treatment they are exposed to (Woodford et al., 2007).

Yet favorable mutations are hard to come by and fairly uncommon. Most mutations that occur in nature are deleterious and unfavorable to the organism, and for natural selection to occur via mutations, these mutations must be beneficial to the organism’s survival. The accumulation of negative mutations also is said to eventually cause extinction of a certain asexual species due to a large amount of acquired genetic load, according to Muller’s ratchet. And because Muller’s ratchet is a consequence of genetic drift, it would make sense that in a certain small population of bacteria the buildup of a single harmful mutation may be detrimental for a certain subspecies.

Favorable mutations in certain bacteria species have also been seen to sometimes have drawbacks and can cause negative effects to the population that it occurs in. In one study performed, it was seen that the mutation that occurred shielding a certain Escherichia coli population from one class of antibiotics actually caused this bacterium to become more sensitive to another class of drugs that was utilized (Recht, et al., 2001). Thus in looking at exactly why this antibiotic resistance is occurring it may not just be a result of mutations. While it may be true that these favorable mutations do occur in bacteria exposed to antibiotic treatments and allow natural selection of a beneficial allele to occur, there must be other underlying genomic factors as well that contribute to this drug resistance.

One factor that seen to possibly have contributed to the evolution of antibiotic resistance is the selection of certain favorable genes in the surrounding environment of a bacteria population. One species of bacteria known as Listeria monocytogenes contain what are known as efflux pumps in their cellular membrane that prevent both antibiotics and heavy metals to get inside the cell. This resistance to treatment is thought to be on account of their environment being tainted with heavy metals (Mata et al., 2000). This shows that organisms selected for certain traits in their growth environment may already be selected for acquired antibiotic resistance before treatment even occurs. Why is this relevant for treatment of other organisms that do not live in harsh environments or are not predisposed to other resistant genes? Bacteria, unlike other organisms, have the ability to transfer already existing genes into their genome through a process known as conjugation. This process allows a certain bacterium to transfer its genes to another bacteria through the transfer of its plasmid. These organisms that are already selected for acquired antibiotic resistance or have been around bacteria that were can then transmit certain genes to other surrounding bacteria in a natural or hospital setting, thus causing other similar organisms to become resistant to a certain treatment and pass this gene on to future generations. In one study, it was found that a number of resistant genes found in different bacteria were discovered to have a comparable DNA sequence to the genome of a species of bacteria known as Streptomyces (Benveniste et al., 1973). Thus it is possible that favorable traits, including favorable mutations, can be cross-transmitted across different species of bacteria causing all kinds of shared resistance to antibiotics and possible cross-evolution across different bacteria species.

This process of mutation and gene transfer between bacteria has also seen to be induced by a number of external factors such as antibiotics. In one study, it was discovered that a species of bacteria known as Vibrio cholerae exhibited what they called an “SOS response” to the addition of an antbiotic known as ciprolaxin and sped up its transfer of genes necessary for resistance (Beaber et al., 2003). This “SOS response” has also been able to be prevented in vivo and has been talked about among scientific circles as being one of the most important aspects in trying to combat antibiotic resistance (Cirz et al., 2005). The reason for this sudden interest on this subject among researchers is that it seems that bacteria, instead of just apathetically hanging on hoping for a stroke of luck to occur, may actually play a part in its own evolution. The answer lies in the way in which the drugs interact with the bacteria during treatment of antibiotics. Quinolone antibiotics are a relatively new class of antibiotics that work by interfering with proteins called topoisomerases, which assist DNA replication by loosening tightly wound DNA and making it accessible. In order to do this, the topoisomerase must initially split the DNA strands and fill in the gaps with a temporary protein bridge. In most cases, the bridge is eliminated and the DNA is reattached after the topoisomerase has done its job, but quinolones bind to this protein bridge and prevent the DNA from resealing. The freed double-strand ends signal that DNA damage has occurred and activate the cell's repair pathway. This DNA damage then sets off the “SOS response”. Researchers suggest that these quinolone antibiotics as well as other antibiotics that cause similar kinds of DNA damage may go on to increase the likelihood that bacteria will evolve resistance and that new generations of drugs will have little chance of succeeding where today's drugs have failed. But new research on this subject has seen that by preventing these SOS response genes from becoming activated, mutations and consequently evolution no longer can occur thus allowing possible treatment on this bacteria (Cirz et al., 2005).

In order to successfully contain the growing monster that is antibiotic resistance, one must get to the heart of the issue, which is in essence is keeping all bacterial evolution at bay. Ironically, the problem researchers have been having when dealing with this issue is that the treatments themselves may actually be the ones controlling bacterial evolution, not the researchers or the health professionals inducing the treatments. The key to this problem may lie in being able to manipulate how mutations and subsequently gene transfer occur in these bacteria, which would essentially give scientists complete control on any kind of natural selection taking place between bacteria. If evolution can somehow be contained, there is still hope down the road of one day seeing this problem under control.

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3) Beaber, John W., Bianca Hochhut, and Matthew K. Waldor. "SOS Response Promotes Horizontal Dissemination of Antibiotic Resistance Genes." Nature 427.6969 (2003): 72-74. Web.

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