Activators of Cylindrical Proteases as Antimicrobials: Identification and Development of Small Molecule Activators of ClpP Protease

SummaryClpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. ClpP on its own can only degrade small peptides. Here, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the ClpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (111 K)Download as PowerPoint slideHighlights► ClpP is a cylindrical protease that requires chaperones to degrade larger proteins ► A screen identified compounds that allow ClpP to degrade larger proteins on its own ► Five structurally distinct compounds were identified that have bactericidal activity ► The compounds stabilized the ClpP double-ring structure