Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their excellent efficacy, optimal dosing strategies to limit their toxicities are still under development. Here, we developed a novel synthetic strategy for fluorine-18-radiolabeled oxazolidinones. As proof-of-concept, we performed whole-body 18 Flinezolid positron emission tomography (PET) in a mouse model of pulmonary TB for noninvasive in situ measurements of time−activity curves in multiple compartments with subsequent confirmation by ex vivo tissue gamma counting. After intravenous injection, 18 F-linezolid rapidly distributed to all organs with excellent penetration into Mycobacterium tuberculosis-infected lungs. Drug biodistribution studies with PET can provide unbiased, in situ drug measurements, which could boost efforts to optimize antibiotic dosing strategies.
Highlights d Optimization of an antitubercular agent afforded gains in solubility and plasma PK d The triazines release intrabacterial NO , as the predominant mechanism of action d The triazines/their intrabacterial metabolites also inhibit InhA and FAS-II pathway
Highlights d A structure-based optimization of the KasA inhibitor DG167 led to JSF-3285 d The inhibitor evolution focused on metabolic stability and mouse plasma PK d JSF-3285 is efficacious in a mouse model of chronic TB infection at 5 mg/kg d JSF-3285 represents a preclinical lead compound for TB
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