Covalent-fragment screening identifies selective inhibitors of multiple Staphylococcus aureus serine hydrolases important for growth and biofilm formation.

is a leading cause of bacteria-associated mortality worldwide. This is largely because infection sites are often difficult to localize and the bacteria forms biofilms which are not effectively cleared using classical antibiotics. Therefore, there is a need for new tools to both image and treat infections.

An mRNA Display Approach for Covalent Targeting of a Virulence Factor.

Staphylococcus aureus () is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed in bacteria, they are valuable targets for diagnostics and therapeutics.

Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of Infections.

() is a major human pathogen that is responsible for a wide range of systemic infections. Since its propensity to form biofilms poses formidable challenges for both detection and treatment, tools that can be used to specifically image biofilms are highly valuable for clinical management. Here, we describe the development of oxadiazolone-based activity-based probes to target the -specific serine hydrolase FphE.

Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of Infections.

is a major human pathogen responsible for a wide range of systemic infections. Since its propensity to form biofilms poses formidable challenges for both detection and treatment, tools that can be used to specifically image biofilms are highly valuable for clinical management. Here we describe the development of oxadiazolonebased activity-based probes to target the -specific serine hydrolase FphE.

Investigating the functional role of a buried interchain aromatic cluster in Escherichia coli GrpE dimer.

Aromatic clusters in the core of proteins are often involved in imparting structural stability to proteins. However, their functional importance is not always clear. In this study, we investigate the thermosensing role of a phenylalanine cluster present in the GrpE homodimer.

Novel Antibacterial Targets in Protein Biogenesis Pathways.

Antibiotic resistance has emerged as a global threat due to the ability of bacteria to quickly evolve in response to the selection pressure induced by anti-infective drugs. Thus, there is an urgent need to develop new antibiotics against resistant bacteria. In this review, we discuss pathways involving bacterial protein biogenesis as attractive antibacterial targets since many of them are essential for bacterial survival and virulence.

A Stutter in the Coiled-Coil Domain of Co-chaperone GrpE Connects Structure with Function.

In bacteria, the co-chaperone GrpE acts as a nucleotide exchange factor and plays an important role in controlling the chaperone cycle of DnaK. The functional form of GrpE is an asymmetric dimer, consisting of a non-ideal coiled coil. Partial unfolding of this region during heat stress results in reduced nucleotide exchange and disrupts protein folding by DnaK.

Small-Molecule Inhibitor Prevents Insulin Fibrillogenesis and Preserves Activity.

Amyloidosis is a well-known but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications and for important mechanistic insights into amyloidogenic pathways.