Tobramycin, an antibiotic commonly used against Pseudomonas aeruginosa bacteria, reduces the bacteria’s load of virulence factors that impair the function of the CFTR (cystic fibrosis transmembrane conductance regulator) protein, a new study shows.
The study, “Tobramycin reduces key virulence determinants in the proteome of Pseudomonas aeruginosa outer membrane vesicles,” was published in the journal PLOS One.
Lung infection by P. aeruginosa is the major cause of lung function decline, morbidity, and mortality among cystic fibrosis (CF) patients. The bacteria have developed several strategies to halt the immune system’s response, including secreting membrane-enclosed bubbles, called outer membrane vesicles, that deliver virulence factors into the lung’s epithelial cells to modify the immune response.
Tobramycin, an inhaled antibiotic, is commonly used to treat P. aeruginosa lung infections in people with CF. The antibiotic improves lung function, and decreases exacerbations. However, despite its therapeutic benefits, tobramycin has a modest impact on reducing P. aeruginosa presence in the lungs.
“These observations led to the suggestion that some of the clinical benefit of tobramycin may be related to anti-inflammatory effects and/or a reduction in the production of virulence factors by P. aeruginosa,” researchers stated.
Researchers investigated whether the mechanisms behind tobramycin’s beneficial effects were linked to a decrease in virulence factors present in outer membrane vesicles released by P. aeruginosa.
Using a particular strain of P. aeruginosa, the team identified 757 proteins present in outer membrane vesicles; of these, 120 proteins were also detected in the vesicles of four other strains of P. aeruginosa. Several of these proteins are known to be directly or indirectly involved in virulence or antibiotic resistance.
Treatment with tobramycin resulted in a statistically significant reduction in protein load of P. aeruginosa‘s outer membrane vesicles, from 294.3 micrograms/ml (control) to 186.3 micrograms/ml (tobramycin-treated).
Tobramycin also significantly decreased the load of 165 proteins, and increased that of 17 proteins in outer membrane vesicles. Several virulence factors, including AprA — a protein that promotes P. aeruginosa survival in the lung — were among those significantly reduced.
Previously, researchers showed that P. aeruginosa‘s outer membrane vesicles impaired the function of the CFTR protein (a defective CFTR protein is the underlying cause of CF), even upon treatment with Vertex Pharmaceuticals’ lumacaftor (VX-809).
Now, researchers showed that tobramycin treatment induces a decrease in the AprA virulence factor in outer membrane vesicles, mitigating the inhibitory effects of the vesicles to the function of CFTR in lung cells when treated with lumacaftor.
Overall, “our proteomic analysis of OMVs (outer membrane vesicles) and biological validation suggest that tobramycin may improve lung function in CF patients infected with P. aeruginosa in part by reducing AprA in OMVs,” the researchers concluded.
The team suggested that by reducing AprA, among other virulence factors in outer membrane vesicles, tobramycin “may reduce lung damage and improve lung function, thereby providing a positive clinical benefit with only a modest reduction in bacterial load.”