Chemical synthesis in the campaign against Gram-negative pathogens

Antimicrobial resistant (AMR) bacteria have proven to pose an increasingly dire threat to humanity over the past several decades. Since the advent of the golden era of antibiotics in the mid twentieth century, resistance mechanisms have become increasingly prevalent in bacteria. This rapid expansion of resistance in contrast to a relatively slow development process of novel antibacterial drugs has created quite a conundrum for medicinal chemists. In the last 50 years, there have been no new classes of antibiotics targeting Gram-negative pathogens. Some estimates even attribute Gram-negative pathogens to being responsible for as high as 75% of all bacteria-related mortalities. Structurally, these pathogens are particularly difficult to target with therapeutics due to the presence of an outer membrane embedded with promiscuous efflux pumps which are absent in Gram-positive pathogens. The first chapter of this dissertation describes efforts towards the total synthesis of darobactin A, a complex bis-macrocyclic heptapeptide which garnered great interest in the chemical biology community. Isolated in 2019 from Photorhabdus khanii, a gut bacterium of entomopathogenic nematodes, darobactin A demonstrated selective and highly potent activity against Gram-negative bacteria. With relatively low isolation yields at the time of initial discovery and novel antimicrobial activity, the compound was an ideal candidate for total synthesis. Completion of the synthesis required the development of the first halogen-selective Larock annulation, two atroposelective strained ring closures, the development of a scalable and robust approach to β,β-disubstituted amino acids, and a global deprotection sequence to remove 9 protecting groups in a single operation. The resulting technologies developed for accessing β,β-disubstituted alanine derivatives would go on to become a separate publication for the utility which the method provides. This chapter also highlights efforts in developing a second generation synthesis which forges the complex bis-macrocyclic framework of darobactin A with a single Larock annulation to perform a one-pot double atroposelective Larock annulation. The second chapter of this dissertation highlights efforts towards a different approach to Gram-negative antibiotics by synthesizing efflux resistant compounds, which can both pass through the outer membrane and accumulate within the cell to kill pathogens. Fabimycin was developed by the Hergenrother lab previously as an eNTRy rule-compliant antibacterial compound which was shown to accumulate within cells and inhibit fatty acid biosynthesis, leading to cell death. While an inspiring lead, Fabimycin lacks the necessary level of accumulation to serve as a pharmaceutical. This work focuses on building on existing SAR efforts to design improved Fabimycin analogues. The third chapter of this document discusses ancillary work performed to synthesize oxidative metabolites of phytocannabinoids. Cannabinoids throughout the 20th century faced serious stigma and thus were underexplored in the therapeutic space. However, in recent decades, biochemical analysis of cannabinoids have revealed that they can have numerous physiological benefits. This work centered around preparing intermediate oxidative cannabinoid observed in mammals to determine their bioactivity in several different studies.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Maturano, Jonathan Daniele

Contributors dc:contributor

• Sarlah, David
• Hergenrother, Paul J
• Denmark, Scott E.
• White, Christina

• Darobactin A
• Total Synthesis

Statement dc:rights

• Copyright 2025 Jonathan Maturano

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129699

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129699