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A new weapon against antibiotic-resistant bacteria

A new weapon against antibiotic-resistant bacteria

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Klebsiella pneumoniae is a type of bacteria that can cause serious infections of the respiratory tract, urinary tract, and other parts of the body. It is a common cause of nosocomial infections and is particularly dangerous for people with weakened immune systems. Klebsiella pneumoniae is resistant to many antibiotics, making it difficult to treat.

UNIGE researchers have discovered that a drug commonly used to treat herpes can fight an antibiotic-resistant bacterium by interfering with its defense mechanisms.

Antimicrobial resistance, or the ability of bacteria to develop resistance to antibiotic treatment, has become a major concern for global health. The World Health Organization (WHO) considers it to be one of the greatest health hazards. Overuse of antibiotics has contributed to the emergence of antibiotic-resistant bacteria, which can lead to serious illness and death. An example of an antibiotic-resistant pathogen is Klebsiella pneumoniae, a bacterium commonly found in hospitals and known for its virulence. Without effective treatment options, we could see a resurgence of diseases like pneumonia and salmonella that were once easily treated with antibiotics.

Researchers at the University of Geneva (UNIGE) have found that edoxudine, an anti-herpes molecule developed in the 1960s, can disrupt the protective surface of Klebsiella bacteria, making them more susceptible to elimination by immune cells. The researchers’ findings were recently published in the journal PLOS ONE.

Klebsiella pneumoniae causes many respiratory, intestinal, and urinary tract infections. Because of its resistance to most common antibiotics and its high virulence, some of its strains can be fatal to 40% to 50% of those infected. There is an urgent need to develop new therapeutic molecules to counteract this.

“Since the 1930s, medicine has relied on antibiotics to get rid of disease-causing bacteria,” explains Pierre Cosson, professor in the Department of Cellular Physiology and Metabolism at UNIGE’s Faculty of Medicine, who led this research. “But other approaches are also possible, including trying to weaken the bacteria’s defense system so that they can no longer escape the immune system. This pathway seems all the more promising as the virulence of Klebsiella pneumoniae largely relies on its ability to evade attack by immune cells.”

An amoeba as a model

To determine whether or not the bacteria were weakened, UNIGE scientists used an experimental model with surprising properties: the amoeba Dictyostelium. This single-celled organism feeds on bacteria by capturing and ingesting them, using the same mechanisms that immune cells use to kill pathogens. “We genetically modified this amoeba so that it can tell us whether the bacteria it encounters are virulent or not. This very simple system then allowed us to test thousands of molecules and identify those that reduced bacterial virulence,” explains Pierre Cosson.

Weakening the bacteria without killing them

Drug development is a long and expensive process with no guaranteed results. UNIGE scientists therefore opted for a faster and safer strategy: reviewing existing drugs to identify potential new therapeutic indications.

The research team evaluated the effect on Klebsiella pneumoniae of hundreds of drugs already on the market across a wide range of therapeutic indications. A drug developed against herpes, edoxudine, proved to be particularly promising. “By altering the surface layer that protects the bacteria from their external environment, this pharmacological product makes them vulnerable. Unlike an antibiotic, edoxudine does not kill the bacteria, which limits the risk of developing resistance, a major benefit of such an antivirulence strategy,” says the researcher.

Although the effectiveness of such a treatment in humans has yet to be confirmed, the results of this study are encouraging: edoxudine acts on even the most malignant strains of Klebsiella pneumoniae and at lower concentrations than those prescribed to treat herpes. “Sufficiently weakening the bacteria without killing them is a subtle strategy, but one that could prove to be a winner in the short and long term,” concludes Pierre Cosson.

Reference: “5-Ethyl-2′-deoxyuridine fragile outer wall of Klebsiella pneumoniae and facilitates intracellular killing by phagocytic cells” by Estelle Ifrid, Hajer Ouertatani-Sakouhi, Tania Jauslin, Sebastien Kicka, Gianpaolo Chiriano, Christopher F. Harrison, Hubert Hilbi, Leonardo Scapozza, Thierry soldi and Pierre Cosson, October 31, 2022, PLOS ONE.
DOI: 10.1371/journal.pone.0269093

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