Repurposing Birabresib to target Gram‑positive bacteria.

The threat of antibiotic-resistant bacteria is rapidly escalating, creating an urgent need for new types of antimicrobials. Although most antibiotics act by disrupting essential cellular processes, such as cell division, replication, transcription, and translation, few novel agents targeting these pathways have been discovered in recent years. So, we pursued a different strategy by searching for molecules that may hyperactivate the ClpP protease, leading to bacterial cell death. ADEP4, a peptide antibiotic, exemplifies this approach by inducing uncontrolled protein degradation via ClpP. Based on key binding sites of ADEP4 on ClpP, we conducted in silico screening using molecular docking, structural chemistry, and pharmacokinetic parameters, primarily evaluating binding affinity (kcal/mol). We identified Birabresib as a promising candidate using this approach. Here, we demonstrate that Birabresib effectively inhibits Gram-positive bacteria, exhibits synergy with the antibiotic rifampicin, and has limited cytotoxicity on the human cell line tested.