Kidney Targeting Smart Antibiotic Discovery: Multimechanism Pleuromutilins for Pyelonephritis Therapy.

Multidrug-resistant (MDR) bacteria pose a global health threat, underscoring the need for new antibiotics. Lefamulin, the first novel-mechanism antibiotic approved by the FDA in decades, showcases pleuromutilins' promise due to low mutation frequency. However, their clinical use is limited by poor pharmacokinetics and organ toxicity. To overcome these limitations, we modified lefamulin's C14 side chain via quaternization and incorporated rigid molecular fragments to enhance pharmacological properties. Introducing a quaternary ammonium group improved liver and kidney targeting via organic cation transporters (OCTs). Candidate 8i, a quaternized imidazo[4,5-c]pyridine pleuromutilin, demonstrated broad-spectrum activity against MDR bacteria, Mycoplasma and Chlamydophila at low doses. 8i targeted transport to infected kidneys, disrupted biofilms, damaged membranes, and inhibited protein synthesis by targeting 50S ribosomal subunit. It cleared rapidly, reducing long-term toxicity. Daily injections were an effective short-course treatment for systemic infections and pyelonephritis. This research presents a novel OCT-mediated, organ-targeted antibiotic design strategy to manage antibiotic-resistant infections.