Browsing by Subject "Gram-Negative Bacteria"
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Item Antisense Blockade of Efflux Systems in Gram-Negative Pathogens(2018-01-23) Subramanian, Naveen G.; Felder-Scott, Christina F.; Sturge, Carolyn R.; Greenberg, DavidAntibiotic resistant bacteria, aka "super bugs", are a critical threat to public health worldwide, as the medical community is running out of effective antibiotics against a growing number of bacteria. One of the ways that bacteria develop resistance to antibiotics is by utilizing efflux systems that are used to pump the antibiotic out. A strategy that is currently being investigated is to restore the susceptibility of these bacteria to antibiotics by using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to suppress genes within these bacteria that encode components of efflux pumps. This project studied the effectiveness of PPMOs that target the AcrAB-TolC efflux pump, which is a major component of the intrinsic antibiotic resistance mechanisms of E. coli and K. pneumoniae. Experiments tested for the effect of the PPMO targeting the acrA gene, specific sequences within the acrA gene, and the tolC gene. The effect of the PPMO was measured by a change in the minimum inhibitory concentration (MIC) of common antibiotics such as Piperacillin/Tazobactam (Pip/Tazo), Azithromycin, and Levofloxacin on strains of these two bacteria. The results show that PPMOs targeted to the acrA gene have a 4-8 fold effectiveness at lowering antibiotic MICs for the bacterial strains. PPMOs that targeted the tolC gene, on the other hand, have no synergistic effect in lowering antibiotic MICs for the bacterial strains. In addition, changing the sequence of the PPMOs targeting the acrA gene was shown to have an effect, albeit small, on susceptibility to antibiotics, which suggests that targeting specific regions of a gene of interest can induce more or less susceptibility in the bacteria to antibiotics.Item Bacterial lipopolysaccharide: toxin or tonic?(1985-10-17) Munford, Robert S.Item Studies Toward the Syntheses of Antiarrythmic, Anti-Virulence, and Anticancer Small Molecules(2015-11-23) Adebesin, Adeniyi Michael; Kürti, László; Falck, John R.; Chen, Chuo; Corey, David R.This work is comprised of three projects: a) the development of antiarrythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid for the treatment of atrial fibrillation, b) the development of potent inhibitors of QseC mediated virulence gene expression, and c) studies toward a biomimetic total synthesis of nigricanoside A. Antiarrhythmic analogs of 17(R),18(S)-epoxyeicosatetraenoic acid (17(R),18(S)-EEQ): Arrhythmias such as atrial and ventricular fibrillation are a leading cause of death in the United States of America. However, the available drugs for the treatment of these deadly conditions can paradoxically induce proarrhythmic effects, amongst other side effects, and are individually insufficient for treatment. Through a neonatal rat cardiomyocyte assay, 17(R),18(S)-EEQ was found to possess negative chronotropic effects, a characteristic of antiarrhythmic activity. My work on this project led to the development of potent and metabolically robust analogs of 17(R),18(S)-EEQ, which are currently being developed by OMEICOS Therapeutics GmbH, an early stage drug development company, for the treatment of atrial fibrillation. Inhibitors of QseC mediated virulence gene expression: Quorum sensing E. coli regulator C (QseC), a membrane-bound histidine sensor kinase, mediates the expression of various virulence genes in Gram-negative bacteria such as Escherichia coli (EHEC), Salmonella typhimurium, and Francisella tularensis which are pathogenic to humans. Therefore, QseC is a potential target of anti-virulence antibacterial strategies. In collaboration with the Sperandio laboratory, my work on this project led to the development of novel inhibitors of QseC mediated virulence gene expression. Some of the analogs synthesized in this project are currently being investigated by GlaxoSmithKline as anti-virulence agents. Studies toward a biomimetic total synthesis of nigricanoside A: Nigricanoside A, a novel ether-linked glycoglycerolipid with 7 unassigned stereocenters, was reported to possess potent (IC50 ≈ 3 nM) antimitotic activity against MCF-7 and HCT-116 cancer cell lines. However, the rarity of the natural product precluded further structural and biological studies. With the aid of biomimetic hypotheses and literature precedents, the Falck laboratory reduced the stereochemical uncertainty associated with the structure elucidation of the nigricanosides. Furthermore, one of the biomimetic hypotheses inspired the development of a novel stereocontrolled distal epoxidation of conjugated dienols. Armed with this methodology, my work on this project led to the synthesis of the three major fragments of a nigricanoside.Item Total Synthesis of Mangrolide A(2018-02-28) Yu, Xueliang; Tambar, Uttam; Ready, Joseph M.; Chen, Chuo; De Brabander, Jef K.The discovery of antibiotics in the 1930s played a critical role in human health by treatment of patients with kinds of infections. During the 'golden era' of antibiotic research, various antibiotics were discovered. The emergence of multi-drug-resistant bacteria has jeopardized the human health. The total synthesis of the natural products plays a crucial part in modern organic chemistry. Mangrolide A was isolated from a rare marine actinomycete strain Actinoalloteichus spitensis by MacMillan and co-workers in 2013. The first part of this thesis will extensively review the synthesis of tiacumicin B which is structurally similar to mangrolide A and also an FDA approved antibiotic. Due to the presence of aminoglycoside in mangrolide A, the glycosylation chemistry of related sugars will also be reviewed. The second part of this thesis is about the total synthesis of mangrolide A and analogs. Base on the studies of MacMillan's group, mangrolide A could not generate the aglycone under acidic conditions. In another path, the desired product mangrolide A methyl ether was achieved along with several rearrangement products. Due to the lack of free hydroxy group at C11, the absolute stereochemistry could not be determined by the standard method (e.g., Mosher's analysis). Synthesis of the desired mangrolide A methyl ether can confirm the stereochemistry and simplify the work of total synthesis of mangrolide A. A rare 2,3-epoxide glycoside was used to install the disaccharide of mangrolide A.