Structure-guided identification of resistance breaking antimalarial N‑myristoyltransferase inhibitorsMore about Open Access at the Crick
Authors listAnja C Schlott Stephen Mayclin Alexandra R Reers Olivia Coburn-Flynn Andrew S Bell Judith Green Ellen Knuepfer David Charter Roger Bonnert Brice Campo Jeremy Burrows Sally Lyons-Abbott Bart L Staker Chun-Wa Chung Peter J Myler David A Fidock Edward W Tate Anthony Holder
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 activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.
Journal Cell Chemical Biology
Issue number 7