Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• The bacterial DNA damage response (SOS) involves RecA and LexA, crucial for DNA repair and mutagenesis.
• Inhibiting the SOS response can sensitize bacteria to antibiotics and reduce resistance.
• Targeting LexA autoproteolysis, unique to prokaryotes, offers a novel therapeutic strategy.

Purpose of the Study:

• To identify small-molecule inhibitors of the RecA/LexA axis, specifically targeting LexA autoproteolysis.
• To establish a framework for academic-industry partnerships in anti-infective drug development.
• To find potential adjuvant therapies to potentiate existing antibiotics.

Main Methods:

• Screening of 1.8 million compounds using a novel fluorescence polarization assay for RecA-induced LexA self-cleavage.
• Follow-up studies using orthogonal assays to validate compound activity.
• Cell-based assays to confirm inhibition of SOS activation.
• Mechanistic assays to elucidate the mode of action.

Main Results:

• Identification of first-in-class small molecules targeting LexA autoproteolysis.
• Demonstrated activity of select compounds in cell-based SOS activation assays.
• Validation of a novel fluorescence polarization assay for high-throughput screening.
• Successful navigation of an academic-industry partnership.

Conclusions:

• First-in-class small molecules targeting bacterial LexA autoproteolysis have been identified.
• These compounds show potential as adjuvants to existing antibiotic treatments.
• The study provides a model for academic-industry collaborations in anti-infective research.
• Further lead optimization could yield novel SOS inhibitors to combat antibiotic resistance.