Ph.D. Thesis Defense
Katherine A. Hurley
Pharmaceutical Sciences, UW-Madison
(under the supervision of Dr. Douglas B. Weibel)
Discovery and Characterization of the Antibacterial Activity of Small Molecules
The discovery of antibiotics had an enormous impact on medicine because it revolutionized medical procedures and prolonged the life expectancy of patients. The unrestricted, yet indispensable, use of antibiotics in clinics has led to the accumulation of infections associated with drug resistant strains of bacteria. The majority of the antibiotics that are commonly utilized were discovered during the ‘golden age’ — the 1940s to 1960s — of antibacterial discovery. Unfortunately, no new classes of antibiotics have been discovered in 29 years. The prevalence of antibiotic resistant bacteria and the lack of discovery have produced a difficult situation that necessitates global attention and collaborative action.
In this thesis, we describe our contribution to filling the antibacterial discovery void. We describe the mechanism of action of a new class of narrow spectrum DNA gyrase inhibitors called the gyramides. The results demonstrate that the gyramides prevent bacterial growth by a mechanism in which the topological state of chromosomes is altered and halts DNA replication and segregation. The specificity and activity of the gyramides for inhibiting gyrase makes these compounds important chemical tools for studying the mechanism of gyrase and the connection between DNA topology and bacterial cell division. We also characterize a new class of broad-spectrum membrane-targeting small molecules: 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxylmethyl)propane-1,3-diol (DCAP) and its hydrophobic analog isopentyl-DCAP (i-DCAP). These small molecules display a unique phenotype, disrupt and increase the fluidity of artificial phospholipid bilayers consisting of bacterial phospholipids. This mechanism of membrane disruption could provide new insight into altering the membrane permeability of gram-negative bacteria. These projects have provided promising small molecules with antibacterial activity and therapeutic potential as antibiotics.
Friday, July 29, 2016
1116 Rennebohm Hall