Peptide Probes of Colistin Resistance Discovered via Chemically Enhanced Phage Display.

Colistin is an antibiotic of last resort used to treat infections caused by multidrug-resistant Gram-negative bacterial pathogens. The recent surge in reported cases of colistin-resistant infections urgently calls for fast and reliable diagnostic methods, which can be used for the facile detection and proper treatment of these challenging infections. A major mechanism of colistin resistance involves phosphoethanolamine (PE) modification of lipopolysaccharide (LPS), the molecular target of colistin.

Versatile Bioconjugation Chemistries of ortho-Boronyl Aryl Ketones and Aldehydes.

Biocompatible and bioorthogonal conjugation reactions have proven to be powerful tools in biological research and medicine. While the advent of bioorthogonal conjugation chemistries greatly expands our capacity to interrogate specific biomolecules in situ, biocompatible reactions that target endogenous reactive groups have given rise to a number of covalent drugs as well as a battery of powerful research tools. Despite the impressive progress, limitations do exist with the current conjugation chemistries.

Phage Display of Dynamic Covalent Binding Motifs Enables Facile Development of Targeted Antibiotics.

Antibiotic resistance of bacterial pathogens poses an increasing threat to the wellbeing of our society and urgently calls for new strategies for infection diagnosis and antibiotic discovery. The antibiotic resistance problem at least partially arises from extensive use of broad-spectrum antibiotics. Ideally, for the treatment of infection, one would like to use a narrow-spectrum antibiotic that specifically targets and kills the disease-causing strain.

Fluorogenic diazaborine formation of semicarbazide with designed coumarin derivatives.

Bioorthogonal fluorogenic reactions serve as enabling tools in research and biotechnology. Herein we describe fluorogenic conjugations of semicarbazide with coumarin derivatives that incorporate a 2-acetylphenylboronic acid motif. These designed coumarins rapidly conjugate with semicarbazide to give diazaborine products with significantly enhanced fluorescence.

Fast and selective labeling of N-terminal cysteines at neutral pH via thiazolidino boronate formation.

Facile labeling of proteins of interest is highly desirable in proteomic research as well as in the development of protein therapeutics. Herein we report a novel method that allows for fast and selective labeling of proteins with an N-terminal cysteine. Although N-terminal cysteines are well known to conjugate with aldehydes to give thiazolidines, the reaction requires acidic conditions and suffers from slow kinetics.

Fast Diazaborine Formation of Semicarbazide Enables Facile Labeling of Bacterial Pathogens.

Bioorthogonal conjugation chemistry has enabled the development of tools for the interrogation of complex biological systems. Although a number of bioorthogonal reactions have been documented in literature, they are less ideal for one or several reasons including slow kinetics, low stability of the conjugated product, requirement of toxic catalysts, and side reactions with unintended biomolecules. Herein we report a fast (>10 M s) and bioorthogonal conjugation reaction that joins semicarbazide to an aryl ketone or aldehyde with an ortho-boronic acid substituent.

Slipping up: partial substrate degradation by ATP-dependent proteases.

ATP-dependent proteases are present in all organisms, where they are responsible for much of intracellular protein degradation. Most proteins are processively unfolded and degraded into small peptides; however, in a few so-called slippery substrates, the protease stalls at a folded domain and releases a large protein fragment. In this review, we describe the properties of physiological slippery substrates that are processed in this manner by ATP-dependent proteases and the recent advances that have been made in understanding the mechanism underlying their partial degradation.