Saturday, November 23, 2019

Arsenic resistance in roundworms and bacteria

Recently, researchers have been looking into arsenic toxicity in roundworms and bacteria. Arsenic trioxide is a compound that has been used as effective treatment of some cancers, including acute promyelocytic leukemia. Despite its success, some patients will experience side effects that are a result of arsenic toxicity.

In order to understand these processes more, researchers looked into strains of bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus) and various wild type species of roundworms. They wanted to find out more about the process of how these organisms are able to tolerate various levels of arsenic trioxide toxicity and how this information could be translated to humans to possibly determine whether or not some people will have a reaction to chemotherapy using arsenic trioxide.

In the various strains of bacteria, the main thing researchers found was that there were three genes that contributed to their arsenic resistance: arsA, arsB, and arsC. Although all three genes code for completely different proteins, the researchers found that all three are needed for the bacteria to express arsenic resistance. There was also a new gene that was discovered in the bacteria, named arsD, which sets an upper limit for the expression of arsA, arsB, and arsC, suggesting that there is a possibility that a high enough dose of arsenic trioxide could still be lethal to bacterial strains with these genes.

In the second paper, researchers decided to study roundworms because of the similarity of their cellular processes to humans. The effects they studied included mitochondrial toxicity, generation of reactive oxygen species, genotoxicity, genome-wide shifts in chromatin structure, reduced lifespan, and induction of a heat-shock response. One of the biggest findings of the paper was the fact that variation in the dbt-1 gene is what causes variation in arsenic trioxide response. The paper also proved that only a single missense variant is needed in the dbt-1 gene to vary the response to arsenic for roundworms. The single missense causes a cysteine to be changed to a serine which causes irreversible changes down the line, reducing the arsenic resistance in the roundworms. As a part of the experiment, the researchers also used CRISPR/Cas-9 genome editing to see if they could revert the roundworms back to their normal state (reverse the missense). This experiment was successful, suggesting that in some cases arsenic trioxide resistance can be altered by altering ones genome.

Overall, I think these studies are really interesting since not many people think about studying roundworms to further cancer studies. Even though some chemotherapies are successful in treating aggressive cancers, they may not always be the best option for the patients. If researchers are able to find pathways coded by genes, it may be possible to test patients and determine their risk of side effects before they begin chemotherapy. Finding specific pathways may also lead to new treatment discoveries. In people who may be exposed to different levels of arsenic trioxide, knowing the molecular pathways may also allow doctors to treat arsenic poisoning more effectively. Using simple model organisms like bacteria and roundworms to be able to make comparisons allow for new doors to be opened for treatments in humans.

Links to the papers:

Orphan enzyme or patriarch of a new tribe: the arsenic resistance ATPase of bacterial plasmids

Natural variation in arsenic toxicity is explained by differences in branched chain amino acid catabolism

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