Discovery of first-in-class nanomolar inhibitors of heptosyltransferase I reveals a new aminoglycoside target and potential alternative mechanism of action.

ABSTRACT: A clinically relevant inhibitor for Heptosyltransferase I (HepI) has been sought after for many years because of its critical role in the biosynthesis of lipopolysaccharides on bacterial cell surfaces. While many labs have discovered or designed novel small molecule inhibitors, these compounds lacked the bioavailability and potency necessary for therapeutic use. Extensive characterization of the HepI protein has provided valuable insight into the dynamic motions necessary for catalysis that could be targeted for inhibition. Structural inspection of Kdo₂-lipid A suggested aminoglycoside antibiotics as potential inhibitors for HepI. Multiple aminoglycosides have been experimentally validated to be first-in-class nanomolar inhibitors of HepI, with the best inhibitor demonstrating a

SUBMITTER: Milicaj J 

PROVIDER: S-EPMC9068772 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature