Indole-based novel small molecules for the modulation of bacterial signalling pathways

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Gram-negative bacteria like Pseudomonas aeruginosa utilize N-acylated L-homoserine lactones (AHLs) for quorum sensing (QS), regulating critical functions including virulence and antibiotic resistance.
• Indole derivatives are known to interfere with bacterial intercellular signaling and can act as inhibitors of QS-dependent phenotypes, offering a complementary approach to traditional antibiotics.
• Targeting QS presents a strategy to combat bacterial infections by disarming pathogens rather than directly killing them, potentially reducing the development of resistance.

Purpose of the Study:

• To design and synthesize novel indole-based N-acylated L-homoserine lactone (AHL) mimics as potential quorum sensing (QS) inhibitors.
• To evaluate the efficacy of these synthesized compounds in inhibiting QS in Pseudomonas aeruginosa.
• To investigate the binding interactions of potent inhibitors with the QS receptor through molecular docking studies.

Main Methods:

• Synthesis of indole-based AHL mimics using carbodiimide-mediated coupling reactions (EDC·HCl and DCC) between aminoindoles and alkanoic acids.
• Inhibition assays using a Pseudomonas aeruginosa QS reporter strain to quantify the reduction in green fluorescent protein (GFP) production.
• Molecular docking simulations to predict the binding affinity and mode of interaction with the target QS receptor protein.

Main Results:

• Several indole-based AHL mimics were successfully synthesized and characterized.
• Compounds 11a, 11d, and 16a demonstrated significant QS inhibition, achieving 44% to 65% reduction in QS activity at a 250 μM concentration.
• Docking studies indicated favorable binding interactions between the synthesized compounds and the QS receptor, supporting their inhibitory mechanism.

Conclusions:

• The synthesized indole-based AHL mimics are effective inhibitors of quorum sensing in Pseudomonas aeruginosa.
• Compounds 11a, 11d, and 16a represent promising lead compounds for the development of new anti-QS antimicrobial strategies.
• This research contributes to the development of novel therapeutic approaches to combat bacterial infections, particularly those involving antibiotic-resistant strains.