Year: 2026
Type: article
Abstract: 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.
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $3,190
Awards: G1512603384, G3246791022, G4661486375, CAREER: Bacterial heterogeneity in stress survival, Collaborative Research: FEC: Establishing Infrastructure for AI-Driven Discovery of Small Molecules to Combat Antibiotic Resistance, Biofilms, and Aflatoxin Contamination, Using a queueing framework to explore the design principles of synthetic circuits in microorganisms, G6671297155
OpenAlex ID: W7160878308
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