APH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.

ABSTRACT: Aminoglycoside-phosphotransferases (APHs) are a class of bacterial enzymes that mediate acquired resistance to aminoglycoside antibiotics. Here we report the identification of small molecules counteracting aminoglycoside resistance in Enterococcus casseliflavus. Molecular dynamics simulations were performed to identify an allosteric pocket in three APH enzymes belonging to 3' and 2'' subfamilies in which we then screened, in silico, 12,000 small molecules. From a subset of only 14 high-scored molecules tested in vitro, we identified a compound, named here EK3, able to non-competitively inhibit the APH(2'')-IVa, an enzyme mediating clinical gentamicin resistance. Structure-activity relationship (SAR) exploration of this hit compound allowed us to identify a molecule with improved enzymatic

SUBMITTER: Kaplan E 

PROVIDER: S-EPMC12005471 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature