A new weapon against antibiotic-resistant bacteria

A new weapon against antibiotic-resistant bacteria
Three compounds affect the interaction between K. pneumoniae and phagocytic amoebae. A. D. discoideum cells were deposited on a lawn of K. pneumoniae and allowed to form a phagocytic plaque for 10 days. B. Phg1A KO cells failed to grow on WT bacteria, but they grew readily on K. pneumoniae mutants with decreased virulence (ΔwaaQ, ΔwbbM) (scale bar: 4mm). C. K2 increased the ability of phg1a KO cells to create phagocytic plaques in comparison with the negative control (DMSO) (scale bar: 4mm). D. The effect of each compound was scored from 4 (visible growth of 1,000 cells) to 0 (no growth of 30,000 cells) and the score of the negative control (DMSO) substracted. In this scale, the result shown in Fig 1C would score as a 0 for DMSO, and 2 for K2. Repeated experiments showed a high variability, but a significant effect for all three selected compounds (mean ± SEM; *: p<0.05; Kruskal-Wallis test, Dunn’s test. DMSO, K2: N = 10; K1, K3: N = 7 independent experiments). The original uncontrasted pictures are shown in S1 Fig in S1 File. E. Chemical structure of the K2 compound. Credit: PLOS ONE (2022). DOI: 10.1371/journal.pone.0269093

The unreasonable use of antibiotics has pushed bacteria to develop resistance mechanisms to this type of treatment. This phenomenon, known as antibiotic resistance, is now considered by the WHO as one of the greatest threats to health. The lack of treatment against multi-resistant bacteria could bring us back to a time when millions of people died of pneumonia or salmonella. The bacterium Klebsiella pneumoniae, which is very common in hospitals and particularly virulent, is one of the pathogens against which our weapons are becoming blunt.

A team from the University of Geneva (UNIGE) has discovered that edoxudine, an anti-herpes molecule discovered in the 60s, weakens the protective surface of Klebsiella and makes them easier to eliminate for immune cells. These results are published in the journal PLOS One.

Klebsiella pneumoniae causes many respiratory, intestinal and urinary tract infections. Due to its resistance to most common antibiotics and its high virulence, some of its strains can be fatal for 40% to 50% of infected people. There is an urgent need to develop new therapeutic molecules to counter it. "Since the 1930s, medicine has relied on antibiotics to get rid of ," explains Pierre Cosson, professor in the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine, who led this research.

"But other approaches are possible, among which trying to weaken the bacteria's defense system so that they can no longer escape the . This avenue seems all the more promising as the virulence of Klebsiella pneumoniae stems largely from its ability to evade attacks from immune cells."

An amoeba as a model

To determine whether or not the bacteria were weakened, the UNIGE scientists used an experimental model with surprising characteristics: the amoeba Dictyostelium. This single-cell organism feeds on bacteria by capturing and ingesting them, using the same mechanisms that use to kill pathogens.

"We genetically modified this amoeba so that it could tell us whether the bacteria it encountered were virulent or not. This very simple system then enabled us to test thousands of molecules and identify those that reduced bacterial virulence," explains Pierre Cosson.

Weakening the bacteria without killing them

Developing a drug is a long and expensive process, with no guarantee of results. The UNIGE scientists therefore opted for a quicker and safer strategy: reviewing existing drugs to identify possible new therapeutic indications. The research team evaluated the effect on Klebsiella pneumoniae of hundreds of drugs already on the market, with a wide range of therapeutic indications. A drug developed to combat herpes, edoxudine, proved particularly promising.

"By altering the that protects the bacteria from their external environment, this pharmacological product makes it vulnerable. Unlike an antibiotic, edoxudine does not kill the bacteria, which limits the risk of developing resistance, a major advantage of such an anti-virulence strategy," says the researcher.

Although the effectiveness of such a treatment in human beings has yet to be confirmed, the results of this study are encouraging: edoxudine acts even on the most virulent 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 terms," concludes Pierre Cosson.

More information: Estelle Ifrid et al, 5-ethyl-2'-deoxyuridine fragilizes Klebsiella pneumoniae outer wall and facilitates intracellular killing by phagocytic cells, PLOS ONE (2022). DOI: 10.1371/journal.pone.0269093

Journal information: PLoS ONE

Citation: A new weapon against antibiotic-resistant bacteria (2022, November 4) retrieved 27 January 2023 from https://phys.org/news/2022-11-weapon-antibiotic-resistant-bacteria.html
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