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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We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

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