Design and Synthesis of a Novel lsoxazoline as a Potential PAM-Agonist

Progression of Alzheimer\u27s disease is associated with a loss of Ml receptor activation in the brain. However, a lack of clinical success following attempts to activate the Ml receptor at the orthosteric site has contributed to a transition towards the allosteric pocket of the receptor. Here, positive allosteric modulators (PAMs) interact to potentiate the acetylcholine response. Recent research proposes that optimization of PAM activity at the expense of intrinsic agonism may posit a means to limit adverse side effects. Therefore, this project proposes a design and synthesis of a novel isoxazoline as a potent PAM agent with weak intrinsic agonism

Siderophore-based detection of Fe(iii) and microbial pathogens

Siderophores are low-molecular-weight iron chelators that are produced and exported by bacteria, fungi and plants during periods of nutrient deprivation. The structures, biosynthetic logic, and coordination chemistry of these molecules have fascinated chemists for decades. Studies of such fundamental phenomena guide the use of siderophores and siderophore conjugates in a variety of medicinal applications that include iron-chelation therapies and drug delivery. Sensing applications constitute another important facet of siderophore-based technologies. The high affinities of siderophores for both ferric ions and siderophore receptors, proteins expressed on the cell surface that are required for ferric siderophore import, indicate that these small molecules may be employed for the selective capture of metal ions, proteins, and live bacteria. This minireview summaries progress in methods that utilize native bacterial and fungal siderophore scaffolds for the detection of Fe(III) or microbial pathogens.Massachusetts Institute of Technology. Dept. of Chemistr

Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

The design, synthesis, and characterization of enterobactin–antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious DiseaseKinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

P-21 Design and Synthesis of a Novel Isoxazoline as a Potential PAM-Agonist

Progression of Alzheimer’s disease is associated with a loss of M1 receptor activation in the brain. However, a lack of clinical success following attempts to activate the M1 receptor at the orthosteric site has contributed to a transition towards the allosteric pocket of the receptor. Here, positive allosteric modulators (PAMs) interact to potentiate the acetylcholine response. Recent research proposes that optimization of PAM activity at the expense of intrinsic agonism may posit a means to limit adverse side effects. Therefore, this project proposes a design and synthesis of a novel isoxazoline as a potent PAM agent with weak intrinsic agonism

Abstracts from international meetings

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