Pleuromutilin and its Application Towards Bidentate Antibiotics: Triazoles, Linker Chemistry, and Serendipitous Discoveries
| dc.contributor.author | Breiner, Logan Michael | en |
| dc.contributor.committeechair | Lowell, Andrew Nesemann | en |
| dc.contributor.committeemember | Santos, Webster | en |
| dc.contributor.committeemember | Mevers, Emily Elizabeth | en |
| dc.contributor.committeemember | Schulz, Michael | en |
| dc.contributor.department | Chemistry | en |
| dc.date.accessioned | 2025-05-29T08:02:31Z | en |
| dc.date.available | 2025-05-29T08:02:31Z | en |
| dc.date.issued | 2025-05-28 | en |
| dc.description.abstract | 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. | en |
| dc.description.abstractgeneral | We are rapidly approaching, and possibly already within, a post-antibiotic era where things as innocuous as a papercut can kill. The rapidity of antimicrobial resistance (AMR) arising is outpacing the creation of new antibiotics. One way of combatting this threat is the use of hybrid antibiotics, as they can have enhanced potency and lowered resistance development. Pleuromutilins are an attractive candidate for hybrid antibiotics, as they have low rates of spontaneous resistance development, and they have two positions which may be easily functionalized: The C22 hydroxyl and C20 vinyl. Additionally, two pleuromutilin based drugs are already on the market. Retapamulin is a topical antibiotic for skin infections, and lefamulin is a orally or intravenously delivered drug for community-acquired pneumonia. The overarching aim of the Lowell lab is the created of hybrid bidentate antibiotics. Bidentate antibiotics are a continuation of the idea of hybrid antibiotics, but designed so that both antibiotics of the hybrid can bind simultaneously with their respective target sites. The beneficial effects of hybrid antibiotics will be retained, and potency may be increased in these bidentate antibiotics as their binding affinity increases. In this work, the sites of functionalization of pleuromutilin are explored to pave the way for their use as bidentate partners. Along the way, several serendipitous discoveries have been made, some of which leading to potent antibiotics in their own right. Finally, pleuromutilins are utilized as bidentate hybrid antibiotics with two other ribosome binding antibiotics: Blasticidin S and azithromycin. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:43880 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/134283 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Antibiotic | en |
| dc.subject | Antimicrobial Resistance | en |
| dc.subject | Natural Product Semi-synthesis | en |
| dc.subject | Ribosome | en |
| dc.subject | Hybrid Drugs | en |
| dc.title | Pleuromutilin and its Application Towards Bidentate Antibiotics: Triazoles, Linker Chemistry, and Serendipitous Discoveries | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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