Misspelling Is Not Necessarily Bad

Author:  Dunia Rassy
Institution:  London School of Hygiene and Tropical Medicine

With its effects costing 18 billion dollars annually just in the United States, any discovery attempting to stop antibiotic resistance in bacteria is warmly welcomed. This time however, the news is not about a new antibiotic, but about taking advantage of bacterial clustered, regularly interspaced, short palindromic repeat (CRISPR) DNA sequences. After scientists misspelled parts of the small DNAs which confer resistance to antibiotics, they discovered CRISPR sequences blocked their entry, avoiding bacteria transformation into resistant strains. The research group belonging to Northwestern University published their results in the renowned journal Science on December 19.

Antibiotic resistance is not a recent problem. In 1943 the first penicillin-resistant species surfaced, spreading rapidly throughout the globe. The problem (besides their dispersal) is that they are becoming resistant to several antibiotics at the same time, limiting the efficacy of treatments. While many new antibiotics are on the pipeline, it is unlikely that we will be able to keep up with bacteria's evolutionary pace. By the time we test new antibiotics, bacteria may already have developed resistance through a mechanism called horizontal transfer. In this mechanism bacteria from the same or different species exchange small circular DNAs called plasmids, which encode antibiotic resistance, allowing them to adapt to new environments.

Dealing with a successful mechanism such as horizontal transfer requires thoughtful solutions to get around it. Luciano A. Marraffini and Erik J. Sontheimer turned their eyes to the CRISPR system, which bacteria use to guard themselves against viral infections. They altered the sequences from a plasmid by exchanging some of its nucleotide bases. When the investigators introduced the plasmid without the modifications into the bacteria Staphylococcus epidermidis, the plasmid did not merge into its genes. On the contrary, the misspelled plasmid matched perfectly to the CRISPR sequences on the bacteria and integrated to its genome. CRISPR sequences seem to act as a lock, opening only to plasmids with useful genes.

Since CRISPR research is very recent, the precise mechanism that denies entry to the plasmids is not known. The study hints at the production of specific RNA molecules by the CRISPR sequences that target the incoming plasmids. The scope of these sequences goes beyond antibiotic resistance; they have given rise to a complete new brand of interference, seeking to block the activity of certain genes. As opposed to the existing RNA interference, this novel technique is based on DNA, which is upstream of RNA in genetic information flow, thus allowing a better control of biological processes.

Although this study was carried using an S. epidermidis, which affects people with weak immune systems, CRISPR interference could be used to fight any pathogen such as the infamous Staphylococcus aureus or anthrax, for example. Yet, researchers will need to apply the findings in order to make progress in the fight against antibiotic resistance, as Dr. Sontheimer points out: "If this mechanism could be manipulated in a clinical setting, it would provide a means to limit the spread of antibiotic resistance genes and virulent factors in staph and other bacterial pathogens".


Written by: Dunia Rassy

Edited by: Jeffrey Kost

Published by: Hoi See Tsao