Date of Completion

2-3-2020

Embargo Period

2-1-2021

Keywords

Antimicrobial Peptides, Host Defense Peptides, Antibiotics, Zinc, Metallonuclease

Major Advisor

Alfredo Angeles-Boza

Associate Advisor

Mark Peczuh

Associate Advisor

Jessica Rouge

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Due to the overuse of conventional antibiotics, coupled with the slow rate of development of novel treatments, antibiotic resistant bacteria have been on the rise. Antimicrobial peptides (AMPs), especially those that bind to biologically relevant metal cations, present an excellent source of potential antibacterial compounds with a low incidence of resistance development. This dissertation explores one such metal binding AMP, the tunicate peptide clavanin A. In the past, clavanin A has been fairly well studied for its activity against the bacterial membrane; however, a fortuitous discovery led us to study clavanin A in the presence of metal ions. We discovered that, in the presence of Zn2+ ions, clavanin A is capable of cleaving bacterial chromosomal DNA, an activity never before reported for a zinc binding AMP. This mechanism of action also has the benefit of improving the antibacterial activity of clavanin A 16-fold. These promising results led to the exploration of AMP mechanisms of action through the application of bacterial cytological profiling. Our study represents the first use of this technique for the study of AMPs. Bacterial cytological profiling allowed us to identify that clavanin A has three distinct mechanisms of action: a membrane-based mechanism at neutral pH that is similar to that of the piscidin peptides, another membrane-based activity at low pH involving strong membrane interaction, and the zinc-based nuclease activity discussed above. The results presented in this dissertation combine to show that not only is clavanin A an interesting AMP system for study, but it is also a prime candidate for the modifications necessary to develop novel peptide-based antibiotic treatments to fend off antibiotic resistant bacteria.

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