Predictions of phenotypic and genotypic adaptations in Pseudomonas aeruginosa biofilms following long-term exposure to an alginate oligomer inhalation therapy

Chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) evolve to generate environmentally adapted biofilm communities, leading to an increased patient morbidity and mortality. OligoG CF-5/20, a low molecular weight inhaled alginate oligomer therapy, is currently in Phase 2b clinical trials in CF patients. Experimental evolution of P. aeruginosa in response to OligoG CF-5/20 was assessed using a bead biofilm model allowing continuous passage (45 days; ~245 generations). Mutants isolated after OligoG CF-5/20 treatment demonstrated fewer small colony variants, which typically had a reduced biofilm forming ability and altered motility profile. Genotypically, OligoG CF-5/20 provided no selective pressure on genomic mutations within morphotypes. Chronic exposure to azithromycin, a commonly prescribed antibiotic in CF patients, ± OligoG CF-5/20 in the biofilm evolution model did not affect acquisition rates of resistance. However, cross-resistance to other antibiotics (e.g. aztreonam) was reduced in the presence of OligoG CF-5/20. Collectively, these findings show that long-term exposure to OligoG CF-5/20 resulted in reduced virulence and improved antibiotic susceptibility of P. aeruginosa.