Discovery of a quorum sensing modulator pharmacophore by 3D small-molecule microarray screening

Area of Science:

• Microbiology
• Drug Discovery
• Biochemistry

Background:

• Traditional small-molecule screening is resource-intensive.
• Bacterial quorum sensing (QS) is crucial for infection and a therapeutic target.
• Modulating QS offers significant clinical potential.

Purpose of the Study:

• To develop and validate a low-cost, 3D microarray platform for high-throughput compound screening.
• To identify novel inhibitors of bacterial quorum sensing.
• To discover biologically active pharmacophores for QS modulation.

Main Methods:

• Development of a 3D microarray-assisted screening platform.
• Screening of quorum sensing analogs using fluorescently labeled LuxR homolog CarR.
• Validation of discovered pharmacophores using fluorometric ligand binding assays and Isothermal Titration Calorimetry (ITC).

Main Results:

• The 3D microarray platform successfully screened thousands of compounds.
• A biologically active chloro-pyridine pharmacophore was discovered.
• Chloro-pyridine analogs potently inhibited N-acyl-homoserine-lactone (AHL)-mediated QS in Serratia (IC50 ≈ 5 μM) and Pseudomonas aeruginosa (IC50 = 10-20 μM).

Conclusions:

• The 3D microarray platform provides an efficient and cost-effective method for drug discovery.
• The chloro-pyridine pharmacophore is a promising lead for developing novel anti-infective agents targeting bacterial quorum sensing.
• This approach has significant potential for rapidly assaying large compound libraries.