A pioneering study by Professor Zhang Fan's team from the School of Pharmaceutical Sciences and the Taikang Center for Life and Medical Sciences at Wuhan University has been published in the esteemed journal Angewandte Chemie International Edition.

The paper, titled "Discovery of Antivirulence ClpP Inhibitors by Self-Resistance Gene-Guided Mining Coupled with Dual Functional Screening”, introduces an innovative approach for the precise and efficient discovery of ClpP inhibitors.

This work offers promising lead compounds for treating MRSA (methicillin-resistant Staphylococcus aureus) and establishes a new paradigm for exploring natural product targets.

MRSA infections have become the leading cause of death from drug-resistant infections, surpassing both hepatitis B and AIDS in mortality rates. While traditional antibiotics can accelerate resistance and disrupt the human microbiome, antivirulence drugs offer a solution by inhibiting bacterial virulence factors, thus reducing pathogenicity and slowing resistance development.

The ClpP protease, a critical protein regulating the virulence of Staphylococcus aureus, is a promising drug target. However, the field faces challenges due to limited structural diversity and a lack of clinical candidates for ClpP inhibitors, highlighting the urgent need for novel, highly active compounds.

Zhang's team employed the ClpP protein Cac16 as a probe to analyze over 34,000 actinomycete genomes, identifying 530 gene clusters with potential ClpP self-resistance genes. From these, 26 clusters were selected for experimental validation.

The team pioneered a dual-functional screening process, leading to the discovery of a new class of ClpP inhibitors, streptoclipamides, from the Streptomyces sp. S186 strain.

Streptoclipamide A demonstrated an IC₅₀ of 480 nM against MRSA-derived ClpP protease and did not affect bacterial growth even at concentrations up to 500 µM, showcasing classic antivirulence properties.

It inhibited the expression of the key virulence factor α-hemolysin and downregulated global virulence regulatory genes, thereby weakening bacterial pathogenicity. Mechanistic studies revealed that streptoclipamide A binds to the ClpP protein, with the Thr72 residue identified as a crucial interaction site.

In MRSA-infected wax moth larvae and mouse pneumonia models, streptoclipamide A, when combined with vancomycin, exhibited significant synergistic effects. This combination increased host survival rates, reduced lung bacterial load, and alleviated tissue damage.