Maternal selenium deficiency during pregnancy in mice increases thyroid hormone concentrations, alters placental function and reduces fetal growth.

Key Points: Inappropriate intake of key micronutrients in pregnancy is known to alter maternal endocrine status, impair placental development and induce fetal growth restriction. Selenium is an essential micronutrient required for the function of approximately 25 important proteins. However, the specific effects of selenium deficiency during pregnancy on maternal, placental and fetal outcomes are poorly understood.

Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase.

A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against and , respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane-permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents.

Identification of Mutations in the Gene Encoding PBP2 That Reduce Carbapenem and Diazabicyclooctane Susceptibility of Escherichia coli Clinical Isolates with Mutations in (PBP3) and Which Carry .

Penicillin-binding proteins (PBPs) are essential for bacterial cell wall biosynthesis, and several are clinically validated antibacterial targets of β-lactam antibiotics. We identified mutations in the gene encoding the PBP2 protein in two clinical isolates that reduce susceptibility to carbapenems and to the intrinsic antibacterial activity of a diazabicyclooctane (DBO) PBP2 and β-lactamase inhibitor. These mutations coexisted with previously described mutations in (encoding PBP3) that reduce susceptibility to monobactams, penicillins, and cephalosporins.

Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones.

Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.