Browsing by Subject "Hydroxyquinolines"

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    Analogues of Nitrofuran Antibiotics are Potent GroEL/ES Pro-drug Inhibitors with Efficacy against Enterococcus Faecium, Staphylococcus Aureus, and Escherichia Coli
    (2020-05) Howe, Christopher Ryan; Johnson, Steven M.; Hoang, Quyen Q.; Meroueh, Samy O.
    In 2019, the ESKAPE pathogens were highlighted by the World Health Organization as some of the most prominent threats to human health, capable of developing significant antibiotic resistance. These pathogens contribute to over 2 million annual infections and ~23,000 annual deaths in the U.S. In addition, various strains of E. coli have also shown a proclivity to develop resistance against common drug classes. The prevalence of these infections highlights an urgency to discover new antibiotics that target previously unexploited pathways essential to bacterial survival. The bacterial GroEL/ES chaperonin system is viewed as a viable antibiotic target. It has been proven essential to bacterial survival and homeostasis under all conditions. Previous studies identified hit GroEL/ES inhibitors with potential antibiotic activity. One promising hit (1) was shown to be a moderate but selective GroEL/ES inhibitor with antibacterial effects against Gram-negative pathogens (K. pneumoniae and A. baumannii). The structural similarity of 1 to known antibiotics – nitroxoline, nifuroxazide, and nitrofurantoin – prompted me to develop two series of hydroxyquinoline and nitrofuran-based analogs. I then assessed these compounds’ abilities to inhibit in vitro GroEL/ES activity, as well as to selectively target ESKAPE/E. coli bacteria over human cells. Initially, I found the nitrofuran analogs were stronger inhibitors of bacterial growth than the hydroxyquinolines, but were weaker at blocking GroEL/ES functions. However, considering nitrofuran-based antibiotics behave as pro-drugs, it was found that they became much more effective GroEL/ES inhibitors when E. coli NfsB nitroreductase was introduced into the GroEL/ES-dMDH refolding assay, metabolizing the nitro groups to their active species. Importantly, lead analogs that potently inhibited bacterial growth exhibited low cytotoxicity to human colon and intestine cells. Although I found E. coli were able to generate varying degrees of irreversible resistance to nifuroxazide, nitrofurantoin, and lead inhibitor 17, perhaps through mutations known to effect NfsA and NfsB nitroreductases, the resulting strains were not necessarily cross-resistant to the other inhibitors. Thus, combination therapy may help bypass these resistance mechanisms. In summary, this study identified key structure-activity relationships to selectively inhibit GroEL/ES and the growth of several bacterial species. Results from this study will aid future efforts to improve inhibitor potency.
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    Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
    (American Diabetes Association, 2017-11) Hernandez-Perez, Marimar; Chopra, Gaurav; Fine, Jonathan; Conteh, Abass M.; Anderson, Ryan M.; Linnemann, Amelia K.; Benjamin, Chanelle; Nelson, Jennifer B.; Benninger, Kara S.; Nadler, Jerry L.; Maloney, David J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.