Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors.

ABSTRACT: The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme

SUBMITTER: Schlott AC 

PROVIDER: S-EPMC6658617 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature