Some bacteria can take on a particular form, known as persistent, which allows them to survive environmental stress by temporarily entering a state of dormancy and then returning to growth once the source of stress has been eliminated. These forms are often responsible for the exacerbation of lung infection in cystic fibrosis (CF). In particular, Pseudomonas aeruginosa can be present in persistent and undiagnosable forms called VBNC, which are able to tolerate antibiotic treatment and cause chronic infections. The role of antibiotics in the development of persistent forms is still being studied.
This project, a continuation of the previous FFC#16/2019 and FFC#13/2017 projects, aimed to evaluate the effectiveness of the new-generation antibiotic cefiderocol in combating lung infections and persistent forms of P. aeruginosa, with a view to using this drug in the treatment of people with CF.
The researchers used bacterial biofilms, i.e., “protective films” formed by bacteria, to study the activity of cefiderocol and the persistence of P. aeruginosa using microbiology and molecular biology techniques: they exposed the samples to both high concentrations of cefiderocol and low concentrations (below the lethal threshold for bacteria) maintained for long periods of exposure. Less development of persistent P. aeruginosa cells was observed in the presence of low concentrations of cefiderocol.
The results obtained were verified using confocal microscopy to observe the biofilms in three dimensions and see how the bacteria organize themselves in the protective film; an in vivo animal infection model was also used (in collaboration with the CFaCore service of FFC Ricerca). In the animal infection model, the presence of persistent cells showed a reduction after antibiotic treatment, and the result was confirmed by confocal microscopy.
Finally, combinations containing known antibiotics and cefiderocol were tested on the bacteria: in particular, the combination of the antibiotic tobramycin with cefiderocol proved to be a promising option for the treatment of P. aeruginosa infections in CF.
These results suggest the need to develop antibiotic therapies that contain combinations of drugs together with cefiderocol. Future studies will aim to identify drugs that enhance the action of this antibiotic and allow the eradication of P. aeruginosa infection.