Bacteria get help from ‘silent’ mutations to evade antibiotics


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“Bacteria get help from ‘silent’ mutations to evade antibiotics”

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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

Researchers looked at the bacteria Klebsiella pneumoniaewhich causes infections in the lungs, blood and wounds of people in hospital, with patients with weakened immune systems, such as those in intensive care units, being particularly vulnerable.

Like many bacteria, K. pneumoniae become 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.

Since increasing resistance to carbapenems could significantly affect our ability to treat infections, people with resistance to carbapenems K. pneumoniae x are classified as “critical” World Health Organization Priority 1 Organisms.

To be effective, antibiotics must penetrate inside the bacteria, and 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 chain 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 Wongfrom 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 the way 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.

Principal Investigator Professor Gad Frankel, from Imperial’s Department of Life Sciences, said: “The mutation has repeatedly evolved independently, which tells us that this new mechanism is not a one-time fluke, but rather driven by the consumption of antibiotics. This suggests that the mutation occurs under antibiotic pressure and accentuates the side effects of excessive antibiotic use in hospitals and other settings.

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

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

Reference: Wong JLC, David S, Sanchez-Garrido J, et al. Recurring appearance of Klebsiella pneumoniae inhibitor-mediated carbapenem resistance compK36 Secondary structure of mRNA. PNAS. 2022;119(38):e2203593119. do I: 10.1073/pnas.2203593119

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