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

ABSTRACT: Among several distinct mechanisms used by bacteria to circumvent antibiotic stress, a predominant form of resistance to ribosome-targeting compounds is the methylation of their ribosomal RNA (rRNA) binding sites. The acquisition of aminoglycoside-resistance methyltransferases that modify 16S rRNA nucleotides in the ribosome decoding center, for example, results in exceptionally high-level aminoglycoside resistance and poses a major threat to their future clinical utility. Here, we report the discovery of a first-in-class panel of small-molecule inhibitors that target a previously unexploited composite "Y-shaped" binding pocket that is unique to the 30S subunit (substrate)-bound form of the 16S rRNA (m¹A1408) methyltransferase NpmA. This Y-shaped pocket, formed by the conserved <

SUBMITTER: Dey D 

PROVIDER: S-EPMC12340973 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature