Understanding molecular evolution is essential for studying the origins of life on Earth, and the adaptations to environmental stressors that allowed for the emergence, survival and evolution of life. Molecular processes that allow organisms the capacity to sense and respond to a range of changes in their immediate environment are not yet all understood. The Last Universal Common Ancestor (LUCA) gave rise to all life, yet it is unknown what processes supported LUCA to overcome a significantly inhospitable to life climate at that time. Prion amyloids, poorly understood, atypical, robust proteins that can store information and cause conformational changes, are highly conserved across phyla yet are most associated with the deadly outcomes they confer in humans. In yeast, they were discovered to function as epigenetic molecular switches to overcome a stressor in the environment. At NASA, the Amyloid World Hypothesis, which states that prion amyloid proteins supported LUCA’s survival, was a highly regarded hypothesis, but a caveat regarding their conservation was that they had not been discovered in Archaea. To answer this question, we systematically searched archaeal proteomes to test if they formed prion amyloids. Our work, establishing for the first time that prion domains of archaeal proteins can form prion amyloids supports the Amyloid World Hypothesis and expands our working knowledge of prion amyloids. The implications of elucidating these sensory and adaptive mechanisms can range from tracing evolutionary lineages of prion amyloids, to understanding how pathogens cause harm to human health as in the case of uropathogenic E. coli (UPEC). To address how UPEC, a World Health Organization critical priority pathogen, responsible for urinary tract infections and nosocomial infections, confers antibiotic resistance against fluoroquinolones, we began by looking at the Quinolone Resistant Determining Regions mutations in a set of 352 clinical isolates. We looked specifically at the gyrA, gyrB, parC, parE genes because they encode the two homologous, type two topoisomerase enzymes DNA gyrase and topoisomerase IV that fluoroquinolones target. To assess the contribution toward overall antibiotic resistance against a panel of 18 fluoroquinolones and 6 non fluoroquinolones, we conducted high throughput minimum inhibitory concentration (MIC) assays to cover 35 concentrations of the most widely observed QRDR mutations of S83L – gyrA, D87N- gyrA of DNA gyrase and S80I – parC on topoisomerase IV. Next, we ran the same testing on clinical isolates for comparison. If the results were similar, we could infer that QRDR mutations and thus target mediated mechanisms on the chromosome are what drive the clinical levels of resistance. If the results are different, then the other mechanisms on the clinical isolates must be contributing to the overall outcomes of resistance; one mechanism alone is not sufficient to provide clinically relevant levels of resistance. The other elements associated with fluoroquinolone resistance found in the clinical genomes were other ABR associated mechanisms like qnr, and aac(6’)-lb-cr, as well as non – QRDR mutations and the presence of Ccdb toxin antitoxin (TA) system. From this result of this work, we can learn more about target mediated fluoroquinolone resistance, and gain more understanding of antibiotic resistance. Our data reveals support for S83L on GyrA as the gateway mutation, as well as the drug specific impact that the 4th QRDR mutation on ParC or ParE respectively. Our data reveals that the triple mutation of S83L, D87N and S80I confers a collective contribution to ABR in our isogenic strains and clinical strains, yet in some cases, ParC or ParE mutations confer a negative impact. Additionally, the differences between the clinical strains with QRDR mutations and isogenic QRDR mutants reveals evidence that clinical levels of resistance rely on multiple mechanistic efforts. This is in line with the phylogenetic analysis of our clinical isolates and others. These results may provide windows of opportunity to better treat these infections in the age of antibiotic resistance and diminished investments in the development of novel antibiotics.