Chemical and chemoenzymatic syntheses of lantibiotics and other bioactive cyclic peptides

New antibiotics are desperately needed to combat the disturbing rise of pathogenic microorganisms resistant to traditional treatments. Throughout the history of modern medicine, natural products have played a leading role as a source and inspiration of new drugs, particularly antibacterial agents. One emerging family of natural products, the lanthipeptides, is defined by the presence of the thioether-containing crosslinks lanthionine and methyllanthionine and includes many members with promising activities against clinically-relevant bacterial pathogens, including drug-resistant strains. These peptides are biosynthesized by translation of a linear precursor peptide on the ribosome, followed by extensive post-translational modification that imparts substantial structural and functional diversity. In order to improve the pharmacological properties of lanthipeptides and therefore foster their clinical application, a more detailed understanding of their biological activities is essential. In this thesis, complementary synthetic platforms have been developed to produce lanthipeptides and analogues, and subsequent biological evaluation has revealed important information about the underpinnings of antibacteria activity in several compounds. In a chemoenzymatic approach described in Chapter II, the activity of an engineered biosynthetic enzyme involved in lacticin 481 maturation was reconstituted in vitro and used to produce a panel of lacticin 481 analogues from synthetic precursor peptides, several of which possessed improved antibacterial potency. This enhanced potency was correlated with improved inhibition of transglycosylation during peptidoglycan biosynthesis. Chapter III describes a chemical approach to lanthipeptide production; solid-phase peptide synthesis was utilized to generate the first reported analogues of the potent lanthipeptide epilancin 15X. These efforts provided the first details into structure-activity relationship analysis of this compound and also established it as a pore-forming agent. The total synthesis of lacticin 481 and analogues containing different crosslink stereochemical configurations was also accomplished, which revealed that the natural crosslink configurations are required for biological activity. In Chapter IV, this solid-supported chemical approach was applied to the generation of potent analogues of the immunomodulatory peptide compstatin via substitution of the reduction-labile disulfide moiety for an isosteric thioether that is stable to reduction. The generality of these synthetic platforms allows for similar engineering approaches in other lanthipeptides and other classes of bioactive cyclic peptides, in order to improve the therapeutic potential of these intriguing compounds.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Knerr, Patrick

Contributors dc:contributor

• van der Donk, Wilfred A.
• Hergenrother, Paul J.
• Katzenellenbogen, John A.
• Nair, Satish K.

• Lantibiotics
• Lanthipeptides
• natural products
• epilancin 15X
• lacticin 481
• LctM
• compstatin
• ribosomally synthesized and post-translationally modified peptides
• RiPPs
• post-translational modification
• cyclic peptides
• antibiotics
• peptide synthesis
• solid-phase peptide synthesis (SPPS)
• biosynthetic engineering
• thioether
• structure-activity relationship
• disulfide engineering

Statement dc:rights

• Copyright 2013 Patrick James Knerr

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/44475

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/44475