Caseinolytic protease (ClpP) is a cylindrical protease that degrades proteins in the presence of ATPase chaperones. On its own, bacterial ClpP can only degrade small peptides; however, the addition of a novel class of antibiotics, ADEPs, can cause unregulated proteolysis leading to bacterial cell death. Bacterial ClpP is an attractive target for antibiotic development. A high-throughput screen of small molecules identified a group of compounds which are termed Activators of Self-Compartmentalizing Proteases (ACP). A collection of ACP3 and ACP4/5 analogs was synthesized and investigated for biological activity. The project resulted in compounds with greater activity than the lead structures against isolated E. coli ClpP. Also, several analogs possessed bacteriostatic activity against N. meningitidis and S. aureus cell lines.

Caseinolytic protease (ClpP) is a cylindrical protease that degrades proteins in the presence of ATPase chaperones. On its own, bacterial ClpP can only degrade small peptides; however, the addition of a novel class of antibiotics, ADEPs, can cause unregulated proteolysis leading to bacterial cell death. Bacterial ClpP is an attractive target for antibiotic development. A high-throughput screen of small molecules identified a group of compounds which are termed Activators of Self-Compartmentalizing Proteases (ACP). A collection of ACP3 and ACP4/5 analogs was synthesized and investigated for biological activity. The project resulted in compounds with greater activity than the lead structures against isolated E. coli ClpP. Also, several analogs possessed bacteriostatic activity against N. meningitidis and S. aureus cell lines.