Synthetic sideromycins (skepticism and optimism): selective generation of either broad or narrow spectrum Gram-negative antibiotics.

New or repurposed antibiotics are desperately needed since bacterial resistance has risen to essentially all of our current antibiotics, and few new antibiotics have been developed over the last several decades. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (i.e.

Siderophore Conjugates of Daptomycin are Potent Inhibitors of Carbapenem Resistant Strains of Acinetobacter baumannii.

Development of resistance to antibiotics is a major medical problem. One approach to extending the utility of our limited antibiotic arsenal is to repurpose antibiotics by altering their bacterial selectivity. Many antibiotics that are used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacterial infections, if they could circumvent permeability barriers and antibiotic deactivation processes associated with Gram-negative bacteria.

A Lewis acid-Lewis base bifunctional catalyst from a new mixed ligand.

Covalent attachment of quinine to a salen framework through a racemic linker gave a new mixed ligand in a 1:1 diastereomeric mixture, from which an active Lewis acid-Lewis base (LA*-LB*) bifunctional catalyst derived from Co(II) was discovered by the screening of metal complexes. The remarkable intramolecular bifunctional catalytic activity (1 mol % catalyst loading) of the new catalyst was demonstrated using a proof-of-principle reaction. [reaction: see text].

Conditional protein alleles using knockin mice and a chemical inducer of dimerization.

We have developed a general method of making conditional alleles that allows the rapid and reversible regulation of specific proteins. A mouse line was produced in which proteins encoded by the endogenous glycogen synthase kinase-3 beta (GSK-3beta) gene are fused to an 89 amino acid tag, FRB*. FRB* causes the destabilization of GSK-3beta, producing a severe loss-of-function allele.

A bifunctional molecule that displays context-dependent cellular activity.

The cell-permeable dihydrofolate reductase inhibitor methotrexate was covalently linked to a ligand for the protein FKBP to create a bifunctional molecule called MTXSLF. The covalent tether between the two ligands was designed to be prohibitively short, so that unfavorable protein-protein interactions between DHFR and FKBP preclude formation of a trimeric complex. In vitro and in vivo experiments demonstrate that MTXSLF is an effective inhibitor of human DHFR, but that efficacy is decreased in the presence of human FKBP due to the high concentration of FKBP and its tight affinity for MTXSLF.