Impact of Growth Conditions on High-Throughput Identification of Repurposing Drugs for <i>Pseudomonas aeruginosa</i> Cystic Fibrosis Lung Infections

• Main Authors: Giovanni Di Bonaventura (Author), Veronica Lupetti (Author), Arianna Pompilio (Author)
• Format: Book
• Published: MDPI AG, 2024-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

<i>Pseudomonas aeruginosa</i> lung infections in cystic fibrosis (CF) patients represent a therapeutic challenge due to antibiotic resistance. Repurposing existing drugs is a promising approach for identifying new antimicrobials. A crucial factor in successful drug repurposing is using assay conditions that mirror the site of infection. Here, the impact of growth conditions on the anti-<i>P. aeruginosa</i> activity of a library of 3386 compounds was evaluated. To this, after 24 h exposure, the survival rate of CF <i>P. aeruginosa</i> RP73 planktonic cells was assessed spectrophotometrically under "CF-like" (artificial CF sputum, pH 6.8, 5% CO₂) and enriched (Tryptone Soya Broth, pH 7.2, and aerobiosis) conditions. Among non-antibiotic compounds (n = 3127), 13.4% were active regardless of growth conditions, although only 3.2% had comparable activity; 4% and 6.2% were more active under CF-like or enriched conditions, respectively. Interestingly, 22.1% and 26.6% were active exclusively under CF-like and enriched conditions, respectively. Notably, 7 and 12 hits caused 100% killing under CF-like and enriched conditions, respectively. Among antibiotics (n = 234), 42.3% were active under both conditions, although only 18.4% showed comparable activity; 9.4% and 14.5% were more active under CF-like and enriched conditions, respectively. Interestingly, 23% and 16.6% were active exclusively under CF-like and enriched conditions, respectively. Sulphonamides showed higher activity under CF-like conditions, whereas tetracyclines, fluoroquinolones, and macrolides were more effective under enriched settings. Our findings indicated that growth conditions significantly affect the anti-<i>P. aeruginosa</i> activity of antibiotics and non-antibiotic drugs. Consequently, repurposing studies and susceptibility tests should be performed under physicochemical conditions that the pathogen tackles at the site of infection.

Item Description

10.3390/antibiotics13070642
2079-6382