Discovery of First-in-Class Inhibitors Targeting a Pathogen-Associated Aminoglycoside-Resistance 16S rRNA...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Bacterial antibiotic resistance is a major global health threat.
• Methylation of ribosomal RNA (rRNA) by methyltransferases confers high-level resistance to antibiotics.
• Aminoglycoside-resistance methyltransferases, like NpmA, modify 16S rRNA, reducing antibiotic efficacy.

Purpose of the Study:

• To discover novel small-molecule inhibitors targeting the 16S rRNA (m1A1408) methyltransferase NpmA.
• To explore a unique 'Y-shaped' binding pocket in NpmA for inhibitor development.
• To establish a new paradigm for developing methyltransferase inhibitors against antibiotic resistance.

Main Methods:

• Molecular dynamics simulations to predict druggable binding sites.
• High-throughput virtual screening of over 2 million compounds.
• Precision docking, chemoinformatics, and iterative experimental analysis of lead compounds and analogs.

Main Results:

• Discovery of a first-in-class panel of small-molecule inhibitors targeting NpmA.
• Identification of three compounds with significant NpmA inhibitory activity.
• Structure-activity relationship analysis revealed key binding interactions, including stereoselectivity and halogen-π interactions.

Conclusions:

• A novel strategy targeting conformationally adaptive, composite binding sites in methyltransferases has been developed.
• This approach provides a promising avenue for combating antibiotic resistance mediated by rRNA methyltransferases.
• The findings could be extended to develop inhibitors for other clinically relevant resistance determinants, such as RmtB.