Antibacterial Discovery via Phenotypic DNA-Encoded Library Screening

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Antimicrobial Resistance

Background:

• Multidrug-resistant infections represent a critical global health threat.
• Existing drug discovery pipelines struggle to identify antibacterial compounds due to limitations in screening libraries.

Purpose of the Study:

• To develop and apply a scalable DNA-encoded library (DEL) with antibacterial-like properties.
• To identify novel inhibitors of bacterial growth using phenotypic screening.

Main Methods:

• Designed and synthesized a 7488-member solid-phase DNA-encoded library (DEL).
• Conducted whole-cell cytotoxicity screens against *Escherichia coli* and *Bacillus subtilis*.
• Utilized hit deconvolution to identify active compounds.

Main Results:

• Identified two low-micromolar inhibitors of *Bacillus subtilis* growth.
• The screening results aligned with known structure-activity relationships of fluoroquinolone antibacterials.
• Demonstrated the feasibility of phenotypic DEL screening for antibacterial discovery.

Conclusions:

• Phenotypic DEL screening is a viable strategy for discovering cell-active antibacterial molecules.
• This approach can overcome limitations of traditional screening libraries.
• The methodology is adaptable for screening against adherent cell types.