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Pseudomonas aeruginosa is an opportunistic pathogenic bacterium present in many ecological niches, such as the roots of plants, stagnant water or the pipes of our homes. Naturally very versatile, it can cause acute and chronic infections that are potentially fatal in people with weakened immune systems. The presence of P. aeruginosa in clinical settings, where it can colonize ventilators and catheters, poses a serious threat. In addition, its adaptability and resistance to many antibiotics make infections by P. aeruginosa more and more difficult to deal with. There is therefore an urgent need to develop new antibacterials.
Scientists at the University of Geneva (UNIGE), Switzerland, have identified a hitherto unknown regulator of gene expression in this bacterium, the absence of which considerably reduces the infectivity of P. aeruginosa and its dangerous nature. These results, to appear in the journal Nucleic Acid Research, could constitute an innovative target in the fight against this pathogen.
RNA helicases perform essential regulatory functions by binding and unwinding various RNA molecules to perform their functions. RNA helicases are found in the genomes of almost all known living organisms, including bacteria, yeasts, plants, and humans; however, they have acquired specific properties depending on the organism in which they are found. “Pseudomonas aeruginosa has an RNA helicase whose function was unknown, but which has been found in other pathogens, ”explains Martina Valentini, researcher at the head of this research at the Department of Microbiology and Molecular Medicine of the Faculty of Medicine of the UNIGE, and holder of an FNS “Ambizione” grant “We wanted to understand what its role was, in particular in relation to the pathogenesis of bacteria and their environmental adaptation.
Severely reduced virulence
To do this, the Geneva team combined biochemical and molecular genetic approaches to determine the function of this protein. “In the absence of this RNA helicase, P. aeruginosa multiplies normally in vitro, both in liquid medium and semi-solid medium at 37 ° C ”, reports Stéphane Hausmann, associate researcher in the Department of Microbiology and Molecular Medicine of the Faculty of Medicine of UNIGE and first author of this study. “To determine if the bacteria’s ability to infect was affected, we had to observe it in vivo in a living organism.”
The scientists then continued their research using the larvae of Galleria mellonella, a model insect, to study host-pathogen interactions. Indeed, the innate immune system of insects has important similarities with that of mammals. In addition, these larvae can live at temperatures between 5 ° C and 45 ° C, which makes it possible to study bacterial growth at different temperatures, including that of the human body. Three groups of hoppers were observed; the first, after injecting a saline solution, saw 100% of its population survive. In the presence of a normal strain of P. aeruginosa, less than 20% survived 20 hours after infection. On the other hand, when P. aeruginosa no longer possessed the RNA helicase gene, more than 90% of the larvae remained alive. “The modified bacteria have become almost harmless, while remaining very much alive,” explains Stéphane Hausmann.
Inhibit without killing
The results of this work show that this regulator affects the production of several virulence factors in bacteria. “Indeed, this protein controls the degradation of numerous messenger RNAs encoding virulence factors”, summarizes Martina Valentini. “From the point of view of antimicrobial drug strategy, deactivating the virulence factors of the pathogen, rather than trying to eliminate the pathogen completely, means allowing the host’s immune system to naturally neutralize the bacteria. and potentially reduce the risk of resistance development. Indeed, if we try to kill the bacteria at all costs, the bacteria will adapt to survive, which favors the appearance of resistant strains. “
The Geneva team is currently continuing its work by screening a series of known drug molecules in order to determine whether one of them has the capacity to selectively block this protein, and to study in detail the inhibition mechanisms on which the development of an effective therapeutic strategy could be based.
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