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As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious Gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. in summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity. acetyicoenzyme A carboxylase | biotin carboxylase | crystal structure | high-throughput screening | fatty acid biosynthesis

Overexpression of plakoglobin, a protein that interacts with both classical and desmosomal cadherins, induces axis duplication in Xenopus frogs. Increased plakoglobin levels may own, generate intracellular signals in the dorsal mesoderm specification. The central arm repeat region of plakoglobin is essential to axis duplication induction and accumulates in the nuclei of embryonic cells.

An analysis of the morphogenesis of Xenopus embryo reveals that functional cytoskeletal components of the cells are the major mediators of the morphogenesis from oocyte to embryo in Xenopus. Cytoskeletal components regulate cellular asymmetries and the integration of forces and signals essential for morphogenesis, helped by several embryonic proteins that regulate gastrulation. The morphogenetic pattern in Xenopus enables its use as a model system for examining 'body language' of embryonic growth.