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.