Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate , based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hit-optimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate was extensively evaluated for its ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The efficacy was evaluated in mice, systemically infected with , where showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.
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