ANTIBIORESISTANCE: An aberrant protein that kills bacterial cells

Because the protein is actually deadly to bacterial cells. The scientists describe how this “misconstructed” protein mimics the action of aminoglycosides, a class of antibiotics. The protein could also serve as a model for a new class of antibiotics.

A new strategy to control bacterial growth

A chance discovery: Initially, the Brookhaven team, which specializes in energy-related research, was far removed from human health and used “just” E. coli bacteria to study genes involved in building plant cell walls, with the aim of converting plant matter (biomass) more efficiently into biofuels. It was during the activation of the expression of a particular plant gene, which allows bacteria to make the protein in question, that the researchers realized that the protein stopped cell growth altogether: “This protein had an extremely toxic effect on cells.

All cells died within minutes of activating gene expression.

A welcome discovery: this discovery could be a piece of the puzzle of the response to antibiotic resistance. “Being able to control the emergence of these bacteria will be increasingly crucial,” explains lead author Paul Freimuth, a biologist at the Brookhaven Institution: “Many scientists fear large-scale epidemics caused by these antibiotic-resistant superbugs”

1. Understand the mechanism of antibiotics: By identifying this protein, which, on its own, is capable of mimicking the effect of a complex mix of aberrant proteins produced during treatment with aminoglycoside antibiotics, the team gains a new way of looking at a mechanism that kills bacterial cells. In fact, the study reveals that the protein itself is not the toxic factor, it is a strand of amino acids, a constituent of the protein, “aberrant” because it is produced by mistake by the ribosomes of the bacteria, which has this effect. The mechanism is reminiscent of aminoglycosides, which force ribosomes to make similar “staging” errors when building proteins.

• One protein is enough: “If a bacterial cell has 50,000 ribosomes, each of which produces a different aberrant protein, is the toxic effect the result of a specific aberrant protein or a combination of several?” This question, which has been debated for decades, has never been resolved. This new work shows, almost by chance, that a single aberrant protein may be enough to exert this toxic effect on bacterial cells.

• How does protein exert its toxic effect? During the production of the aberrant protein, the initial step of protein quality control is well activated, but the later steps of the process necessary for the degradation of the aberrant proteins are blocked. Furthermore, it is the rate of production of the aberrant protein that allows cell death: when cells contain many copies of the gene that encodes the aberrant plant protein, the cellular quality control machinery correctly detects the protein irregularity but is unable to to break it. lower it completely. On the other hand, when the number of copies of the gene that encodes the protein is reduced, then the cell’s quality control system manages to eliminate the toxic protein and the bacterial cells survive. The process is very similar to that seen in cells treated with sublethal doses of aminoglycoside antibiotics. If the dose is insufficient, the cell quality control response is activated, but not enough and the cells can still continue to grow.

2. Development of a new family of inhibitors able to reproduce this effect of protein d in the cell, this is the team’s second goal: “The next step will be to determine the structures of our protein, how it communicates with membrane channels and how it kills bacterial cells, in order to design new drugs with similar effects.”