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Rational Design of Benzo-Dioxygenated FabH Inhibitors Unveiled by Proteomic Profiling: Broad-Spectrum Antibacterial Activity and In Vivo Therapeutic Efficacy

ABSTRACT: 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.

ORGANISM(S): Escherichia Coli

SUBMITTER: Rui Wang

PROVIDER: PXD064801 | iProX | Tue Jun 10 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Tan2012 - Antibiotic Treatment, Inoculum Effect The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies. This model is described in the article: The inoculum effect and band-pass bacterial response to periodic antibiotic treatment. Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L. Mol Syst Biol. 2012 Oct 9; 8:617 Abstract: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes. This model is hosted on BioModels Database and identified by: MODEL1208300000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Rational Design of Benzo-Dioxygenated FabH Inhibitors Unveiled by Proteomic Profiling: Broad-Spectrum Antibacterial Activity and In Vivo Therapeutic Efficacy

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