In vitro and in vivo characterization of noso-502, a novel inhibitor of bacterial translation

Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem- resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum β-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED50) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile

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ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Electro-precipitation via oxygen reduction : a new technique for thin film manganese oxide deposition

Manganese oxide was deposited from a non-aqueous solution, dimethyl sulfoxide (DMSO), via the reduction of dissolved oxygen. The formed superoxide radical ion (O-2(-center dot)) reacts rapidly with the manganese ions forming a smooth and thin film (80 nm) of manganese oxide. From an in situ EQCM study, it could be concluded that MnO2 was the most probable oxide which was deposited at an average growth rate of 0.049 mu g s(-1) or 0.077 nm s(-1). Since the direct deposition of a phase pure MnO2 layer was not confirmed by XRD, it is more likely that a variety of manganese oxides has been deposited during the electro-precipitation reaction and thus further optimization or post-treatments are required to obtain an active manganese oxide layer for thin film deposits. The key property of this new deposition technique is the self-limiting behavior, proven by rotating ring-disk electrode experiments. This is crucial to electrodeposit thin films conformally on high aspect ratio structures for 3D all-solid-state lithium-ion batteries or supercapacitors

Synthesis and spectroscopic characterization of enantiopure protected trans-4-amino-1-oxyl-2,2,6,6-tetramethyl piperidine-3-carboxylic acid (trans \u3b2-TOAC)

Enantiomerically pure (3R,4S) and (3S,4R) protected 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acids were synthesized by reduction of the enamines resulting from the condensation of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone with (R) or (S)-alpha-methylbenzylamine. While NaBH3CN/CH3COOH reduction gave predominantly a mixture of the two possible cis-diastereomers, the use of NaBH4/(CH3)(2)CHCOOH resulted in a mixture of only one trans- and one cis-diastereomer. Removal of the chiral auxiliary from the separated diastereoisomers by hydrogenolysis and regeneration of the nitroxide radical gave the desired beta-amino, esters. The ESR spectrum of the (3R,4S)-enantiomer is also reported. (c) 2005 Elsevier Ltd. All rights reserved

Synthesis of enantiomerically pure cis- and trans-4-amino-l-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acid: A spin-labelled, cyclic, chiral beta-amino acid, and 3D-Structural analysis of a doubly spin-labelled beta-hexapeptide

Amination of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone (1) with either (R)- or (S)-\u3b1-methylbenzylamine gave corresponding enamines 2. Whereas the reduction with NaBH3CN/CH3COOH afforded predominantly a mixture of two possible cis diastereomers of 3, (1\u2032R,3S,4S)/(1\u2032R,3R,4R) or (1\u2032S,3R,4R)/(1\u2032S,3S,4S), which could be separated by crystallisation of their HCl salts, the use of NaBH4/(CH3)2CHCOOH as the reducing agent resulted in a mixture of one trans- and one cis diastereomer of 3 (1\u2032R,3S,4R)/(1\u2032R,3R,4R) or (1\u2032S,3R,4S)/(1\u2032S,3S,4S) in varying proportions depending upon the conditions used. The stereochemistry of the four diastereomers of 3 was clearly established by X-ray diffraction analysis of one of them, combined with 1H NMR spectroscopic studies after nitroxide reduction. Removal of the chiral auxiliary from the separated diastereomers of 3 by hydrogenation and regeneration of the nitroxide radical gave expected amino esters 4. A model \u3b2-hexapeptide containing (3R,4S)-\u3b2-TOAC combined with (1S,2S)-2-aminocyclohexane carboxylic acid was synthesised by solution methods and its preferred conformation (314-helix) was assessed by FTIR absorption, CD, and EPR spectroscop