‘Silent’ mutations help bacteria evade antibiotics

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WT(25c > t) induces a rod involving the SDS. (A) Normalized DMS signal side-by-side by nucleotide in SDS from full-length in vitro transcribed and refolded ompK36WTompK36WT(25c > t) ompk36WT(24&25c > t) and ompK36WT not processed by DMS. Higher values ​​correspond to increased database accessibility. The DMS signal (±SD) of 2 biological repeats for nucleotides -14a to -10g is shown. (B–D). DMS constrained structure models of the 5′ end of ompK36WT (B), ompK36WT(24&25c > t) (C) and ompK36WT(25c) > t) (D). The nucleotides are stained by the normalized DMS signal. SDSs in RNA structures are highlighted in gray. Arrows indicate position −14 and position 25c > t in ompK36WT(25c > t). Credit : Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2203593119″ width=”800″ height=”530″/>

Position 25 in ompK36WT(25c > t) RNA induces a link involving the SDS. (A) Side-by-side normalized DMS signal per nucleotide in SDS from in vitro transcribed, full-length folded ompK36WTcompK36WT(25c > t)ompk36WT(24&25c > t)and ompK36 not treated with DMSWT. Higher values ​​correspond to increased database accessibility. The DMS signal (±SD) of 2 biological repeats for nucleotides -14a to -10g is shown. (B–D). DMS stress structure models of the 5′ end of ompK36WT (B), ompK36WT(24&25c > t) (C) and ompK36WT(25c > t) (D). The nucleotides are stained by the normalized DMS signal. SDSs in RNA structures are highlighted in gray. Arrows indicate position −14 and position 25c > t in ompK36WT(25c > t). Credit: Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2203593119

Researchers have discovered a new way that nosocomial infections resist antibiotics, thanks to a “silent” genetic mutation.

Bacteria can acquire antibiotic resistance through random mutations in their DNA that give them an advantage that helps them survive. Finding genetic mutations and discovering how they help bacteria survive an antibiotic attack is key to helping us fight back with new drugs.

Researchers have just discovered a “silent” mutation in the genetic code that leads to antibiotic resistance. Typically, mutations of this type would be overlooked and they may already be present in other infectious bacteria.

The team, led by researchers from Imperial College London and including international collaborators, published their findings today in the journal Proceedings of the National Academy of Sciences.

Growing resistance

The researchers looked at the bacterium Klebsiella pneumoniae, which causes infections in the lungs, blood and wounds of hospitalized people, with patients with weakened immune systems, such as those in intensive care units, being particularly vulnerable.

Like many bacteria, K. pneumoniae is becoming increasingly resistant to antibiotics, particularly to a family of drugs called carbapenems. These important last resort drugs are used in hospitals when other antibiotics have already failed.

Because growing resistance to carbapenems could significantly affect our ability to treat infections, carbapenem-resistant K. pneumoniae are classified as World Health Organization Priority 1 “critical” organisms.

To be effective, antibiotics must get inside bacteria, and in K. pneumoniae this happens through a channel in the bacteria’s outer membrane, formed by a protein called OmpK36. The team discovered a genetic mutation that causes the bacteria to produce less protein, effectively closing some of these channels and preventing the carbapenem antibiotics from entering.

“Silent” Mutations

This mutation, however, works differently from standard mutations that lead to antibiotic resistance. Usually, mutations change the genetic code so that when it is “read” by ribosomes and converted into protein, it produces a different string of amino acids with different functions.

This mutation still produces the same chain of amino acids, but changes the structure of an important mRNA intermediate, preventing ribosomes from reading the code and making proteins from it.

When looking for mutations, genomic techniques usually look for changes in the amino acid sequence. However, since this mutation changes a structure, rather than the sequence itself, it could be considered a “silent” mutation.

First author Dr Joshua Wong, from Imperial’s Department of Life Sciences, said: “In the age of big data and genomics, mutations such as the ones we have discovered can be considered ‘ silent”, because the genetic code results in the same protein sequence. .

“This finding should change the way we view the genetic code of bacteria and potentially indicates that we in the scientific community have overlooked other similar mutations that may have important effects. Our work focuses on a single mutation but fundamentally changes how we interpret mutations, especially those once thought to be silent.”

Driven by the use of antibiotics

The Imperial team, which characterized the mutation, worked with teams from the University of Oxford, the University of Florence and Harvard University to identify the distribution of the mutation around the world, assess resistance levels and determine how the mutation has affected the intermediate mRNA. structure.

Using data from samples of resistant bacteria collected around the world, the team showed that the mutation occurred multiple times independently. This suggests that it is not random and is instead driven by the bacterium’s need to defend itself against antibiotics.

Lead researcher Professor Gad Frankel, from Imperial’s Department of Life Sciences, said: “The mutation has repeatedly evolved independently, and this tells us that this new mechanism is not a fluke. punctual, but rather motivated by the consumption of antibiotics. suggests that the mutation occurs under antibiotic pressure and highlights the side effects of overuse of antibiotics in hospitals and other settings.”

The team now hopes their discovery will be incorporated into bioinformatics tools that analyze genetic sequences to identify the presence of the mutation, as was done with an earlier mechanism discovered by the team.

They will also continue to work with their collaborators to search for other important mutations in this key pathogen.


Common drug-resistant superbug develops rapid resistance to ‘last resort’ antibiotic


More information:
Joshua LC Wong et al, Recurrent emergence of carbapenem resistance from Klebsiella pneumoniae mediated by an ompK36 mRNA inhibitory secondary structure, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2203593119

Provided by Imperial College London


Quote: ‘Silent’ Mutations Help Bacteria Evade Antibiotics (September 19, 2022) Retrieved September 20, 2022 from https://phys.org/news/2022-09-silent-mutations-bacteria-evade-antibiotics.html

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