Breiner, Logan Michael2025-05-292025-05-292025-05-28vt_gsexam:43880https://hdl.handle.net/10919/134283The world is facing a global antimicrobial-resistance (AMR) crisis. Classes of antibiotics continually face ineffectiveness as resistance mechanisms in microbes develop and propagate. The semi-synthetic derivatization of natural product antibiotics has provided many of our treatments, but new treatments are a constant necessity. The pleuromutilin antibiotics constitute a class of diterpenoid, ribosome-inhibiting antibiotics. Pleuromutilins have been developed into a number of veterinary antibiotics, as well as two FDA approved drugs, retapamulin and lefamulin. This class exhibits a low propensity to resistance development. This dissertation reports progress in rational design, synthesis, and testing of pleuromutilin derived antibiotics. Among these new classes of pleuromutilins are the 20-triazolyl-12-epi-pleuromutilins, 22-S-oligoethylene glycol pleuromutilins, and two pleuromutilin based bidentate hybrid antibiotics: The pleuromutilin-blasticidins, and the pleuromutilin-azithromycins. Within these new classes, we found highly potent representatives which now serve as lead compounds for future structure activity relationship studies and development. Additionally, unexpected activity against P. falciparum has resulted in a new project pursuing pleuromutilin antimalarials.ETDenIn CopyrightAntibioticAntimicrobial ResistanceNatural Product Semi-synthesisRibosomeHybrid DrugsDissertation