Pleuromutilin and its Application Towards Bidentate Antibiotics: Triazoles, Linker Chemistry, and Serendipitous Discoveries

The 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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Chemistry

Department dc:contributor.department

Chemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2025

Author dc:creator

• Breiner, Logan Michael

Chair dc:contributor.committeechair

• Lowell, Andrew Nesemann

Committee members dc:contributor.committeemember

• Santos, Webster
• Mevers, Emily Elizabeth
• Schulz, Michael

• Antibiotic
• Antimicrobial Resistance
• Natural Product Semi-synthesis
• Ribosome
• Hybrid Drugs

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:43880

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/134283