Structural features of fluoroquinolone-class antibiotics that affect lethal activities and DNA binding

• Main Author: Schwanz, Heidi Ann
• Other Authors: Kerns, Robert J.
• Format: Others
• Language: English
• Published: University of Iowa 2012
• Subjects: antibiotics; fluoroquinolone resistance; fluoroquinolones; quinazoline; structure activity relationships; topoisomerases; Pharmacy and Pharmaceutical Sciences
• Online Access: https://ir.uiowa.edu/etd/1395; https://ir.uiowa.edu/cgi/viewcontent.cgi?article=5434&context=etd

Fluoroquinolones, broad-spectrum bactericidal antibiotics, exert their effects by inhibiting type II topoisomerases through the formation of a fluoroquinolone-DNA-topoisomerase ternary complex. Recently, newer, structurally unique fluoroquinolones have been shown to kill bacteria by promoting chromosomal fragmentation in the presence and absence of protein synthesis, thus allowing fluoroquinolones to potentially be used in the treatment of microorganisms that go into a dormant state. There is a need to further understand the structure activity relationships (SAR) of fluoroquinolones to develop new antibiotics that can kill dormant bacteria and are active against current resistant strains. The hypothesis that structurally unique fluoroquinolones interact with the DNA- fluoroquinolone-topoisomerase ternary complex in a unique way that leads to different killing pathways is the basis of this work. The first approach to understand SAR for fluoroquinolones to kill non-growing bacteria was to evaluate the effect of modifications at the C-8 and C-5 positions on lethality. Novel, synthetically-derived and commercially-available fluoroquinolones were evaluated for ability to kill Escherichia coli in the presence and absence of chloramphenicol, a known protein synthesis inhibitor used to simulate non-growing bacteria. The second study was to understand SAR of fluoroquinolone-class agents necessary to maintain antibacterial activity against common fluoroquinolone resistance-causing bacterial mutations on topoisomerase IV. A panel of novel fluoroquinolones, 2,4-quinazoline diones, and fluoroquinolone-like analogues with unique substitution combinations at C-8 and C-7 was synthesized and evaluated for ability to poison wild-type and mutant Bacillus anthracis topoisomerase IV. The third study to understand the contribution of SAR of fluoroquinolone-class agents to novel killing mechanisms was to evaluate the binding interaction of fluoroquinolones to double-stranded and nicked DNA. Binding affinities of fluoroquinolones to DNA were determined; fluoroquinolones were found to bind different DNA types with varied affinities. The ability of a series of C-8 and C-7 modified fluoroquinolones to stabilize or destabilize DNA was assessed. The results of these studies also add broadly to the understanding of SAR associated with fluoroquinolone-class antibiotics for killing in the presence and absence of protein synthesis, maintaining activity in the presence of resistance-causing mutations in the target enzymes, and increasing binding interactions with different types of DNA.