ABSTRACT:
The clinical significance of
Pseudomonas aeruginosa
infections and the tolerance of this opportunistic pathogen to antibiotic therapy makes the development of novel antimicrobial strategies an urgent need. We previously found that D,L-malic acid potentiates the activity of ciprofloxacin against
P. aeruginosa
biofilms grown in a synthetic cystic fibrosis sputum medium by increasing metabolic activity and tricarboxylic acid cycle activity. This suggested a potential new strategy to improve antibiotic therapy in
P. aeruginosa
infections. Considering the importance of the microenvironment on microbial antibiotic susceptibility, the present study aims to further investigate the effect of D,L-malate on ciprofloxacin activity against
P. aeruginosa
in physiologically relevant infection models, aiming to mimic the infection environment more closely. We used
Caenorhabditis elegans
nematodes,
Galleria mellonella
larvae, and a 3-D lung epithelial cell model to assess the effect of D,L-malate on ciprofloxacin activity against
P. aeruginosa
. D,L-malate was able to significantly enhance ciprofloxacin activity against
P. aeruginosa
in both
G. mellonella
larvae and the 3-D lung epithelial cell model. In addition, ciprofloxacin combined with D,L-malate significantly improved the survival of infected 3-D cells compared to ciprofloxacin alone. No significant effect of D,L-malate on ciprofloxacin activity against
P. aeruginosa
in
C. elegans
nematodes was observed. Overall, these data indicate that the outcome of the experiment is influenced by the model system used which emphasizes the importance of using models that reflect the
in vivo
environment as closely as possible. Nevertheless, this study confirms the potential of D,L-malate to enhance ciprofloxacin activity against
P. aeru
ginosa-associated infections.