ABSTRACT
The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.