{"database":"iProX","file_versions":[],"scores":null,"additional":{"omics_type":["Proteomics"],"submitter":["Rui Wang"],"species":["Escherichia Coli"],"full_dataset_link":["http://www.iprox.org/page/project.html?id=IPX0012231000"],"submitter_email":["wangrui@szbl.ac.cn"],"submitter_affiliation":["shenzhen bay laboratory"],"sample_protocol":[""],"repository":["iProX"],"data_protocol":[""],"additional_accession":[]},"is_claimable":false,"name":"Rational Design of Benzo-Dioxygenated FabH Inhibitors Unveiled by Proteomic Profiling: Broad-Spectrum Antibacterial Activity and In Vivo Therapeutic Efficacy","description":"The global escalation of antibiotic-resistant bacterial infections poses a life-threatening challenge to public health, necessitating the urgent development of innovative antibiotics targeting unexploited metabolic vulnerabilities. Through rational design, we developed a series of benzo-dioxygenated FabH inhibitors targeting the bacterial fatty acid biosynthesis pathway. Guided by active-site analysis and pharmacophore-guided optimization, we engineered a Y-shaped scaffold that achieved nanomolar inhibition of FabH (IC50 = 1.90 µM). The lead compound F35 showed broad-spectrum efficacy with MIC values as low as 1.56 µg/mL against Gram-negative and Gram-positive pathogens, outperforming Kanamycin B. Structural analysis revealed key interactions between FabH conserved residues and fluorine-mediated halogen bonding. In vivo assay, F35 accelerated wound closure in S. aureus-infected rodents, demonstrating a favorable biocompatibility. Our study establishes a convergence paradigm that integrates structure design, chemoproteomic identification, and therapeutic development for antibiotics, providing a strategic blueprint to combat multidrug resistance via precision targeting of metabolic chokepoints in bacterial pathogens.","dates":{"publication":"Tue Jun 10 00:00:00 GMT+01:00 2025"},"accession":"PXD064801","cross_references":{"TAXONOMY":["562"]}}