Assay-Based High Throughput Screening of Diverse Libraries Identifies Selective Inhibitors of Staphylococcus aureus...

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Bacterial ribonuclease P (RNase P) is a crucial ribonucleoprotein enzyme essential for bacterial survival.
• RNase P is a promising target for novel antibiotic development due to its essentiality.
• Discovering potent and specific RNase P inhibitors has been challenging despite previous screening efforts.

Purpose of the Study:

• To explore broader chemical space for novel scaffolds targeting bacterial RNase P.
• To identify selective inhibitors of *Staphylococcus aureus* RNase P.

Main Methods:

• Screening of commercial RNA-targeted and protein mimetic compound libraries against *S. aureus* RNase P.
• Structure-activity relationship (SAR) analyses to determine the active pharmacophore.
• Assessing selectivity by comparing IC50 values against RNase P from different bacterial species.

Main Results:

• Identification of five distinct chemical scaffolds exhibiting micromolar IC50 values against *S. aureus* RNase P.
• Discovery of two compounds sharing an amide scaffold and a tetrahydroisoquinoline group.
• Two identified compounds demonstrated selectivity, inhibiting *S. aureus* RNase P more effectively than RNase P from *Escherichia coli* and *Enterococcus faecium*.

Conclusions:

• Expanding chemical space screening can uncover novel scaffolds for targeting essential bacterial enzymes.
• The identified scaffolds represent potential starting points for developing selective RNase P inhibitors.
• This study provides a foundation for developing new antibiotics targeting bacterial RNA processing.