Identification of ClpP Dual Isoform Disruption as an Antisporulation Strategy for Clostridioides difficile.

The Gram-positive bacterium Clostridioides difficile is a primary cause of hospital-acquired diarrhea, threatening both immunocompromised and healthy individuals. An important aspect of defining mechanisms that drive C. difficile persistence and virulence relies on developing a more complete understanding of sporulation.

Clostridium difficile ClpP Homologues are Capable of Uncoupled Activity and Exhibit Different Levels of Susceptibility to Acyldepsipeptide Modulation.

Caseinolytic protease P (ClpP) has emerged as a promising new target for antibacterial development. While ClpPs from single isoform expressing bacteria have been studied in detail, the function and regulation of systems with more than one ClpP homologue are still poorly understood. Herein, we present fundamental studies toward understanding the ClpP system in C.

Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides.

The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram-positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain.

Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P.

Caseinolytic protease P (ClpP) maintains essential roles in bacterial homeostasis. As such, both the inhibition and activation of this enzyme result in bactericidal activity, making ClpP a promising target for antibacterial drug development. Herein, we report the results of a fluorescence-based screen of ∼450 structurally diverse fungal and bacterial secondary metabolites.