Thiazole derivative based topical nanoemulgel for inhibition of bacterial virulence in surface infections

Objective(s): Antimicrobial resistance emerged as a global challenge owing to limited therapeutic options to control infections. Pseudomonas aeruginosa, an MDR pathogen already developed resistance against many conventional antibiotics. An “anti-virulence strategy” that targets bacterial virulence rather than growth proves effective against drug-resistant pathogens. Materials and Methods: Here, we used a structure-based drug design approach to identify lead molecules using the LasR receptor protein of P. aeruginosa as a target responsible for virulence production in this bacterium. From the identified hits, we developed lead-based nanoformulation and investigated its effectiveness for treating the P. aeruginosa associated surface-infection in-vivo. First, TC-based nanoemulsions were fabricated by high-pressure homogenization and evaluated for various in vitro parameters. The optimized nanoemulsions were thereby utilized to prepare NEG.Results: The nanoemulsion (F۳) exhibited low droplet size (۵۱.۰۴±۱.۸۸ nm), PDI (۰.۰۶۵±۱.۱۴), and negative zeta potential (-۳۳.۶۵±۰.۸۲ mV). In animals, topical application of NEG-۳ demonstrated significant improvement on skin permeability (۴۵۹±۱۰.۱۷ µg), drug influx (۱۸.۹۹±۰.۷۶ μg/cm۲ hr), and repressed the CFU of P. aeruginosa induced-surface infection (P≤۰.۰۰۱). The histology of rat skin demonstrated a significant effect for groups treated with TC-based NEGs as compared with a negative control group, whereas no significant effect was seen on rat liver indicating low systemic exposure to the drug. Also, NEG۳ showed no significant changes under different stability conditions after ۳ months.Conclusion: TC-based NEGs open up the possibility of a more effective way to combat serious surface infections caused by P. aeruginosa.

Keywords:

Anti-virulent strategy , Drug-resistance , LasR , Nanoemulgel formulation , Pseudomonas aeruginosa , Thiazole compound