A Novel Antimalarial Agent that Inhibits Protein Synthesis in <i>Plasmodium falciparum</i>
Abstract
Abstract The emergence of drug resistance to nearly all antimalarials following their rollout underscores the need for novel chemotypes with novel modes of action to replenish the antimalarial drug‐development pipeline. We identified a novel class of compounds in the antimalarial armory. Compound 31 , characterized by a 2‐hydroxyphenyl benzamide scaffold, displays potent activity against blood‐stage and mature sexual stages of Plasmodium falciparum and no toxicity in human cells. Resistance selection studies with 31 identified a previously unknown point mutation in the P. falciparum multidrug‐resistance protein 1 ( pfmdr1 ) gene, for which we confirmed causality by CRISPR/Cas9‐based gene editing as the primary mediator of resistance. No cross‐resistance toward first‐line antimalarials was identified in compound 31 ‐resistant parasites. Proteomics studies indicated that the primary mode of action of 31 is through direct binding to cytosolic ribosomal subunits, thereby inhibiting protein synthesis in the parasite. Taken together, compound 31 is a promising starting point for the development of a next‐generation antimalarial.
Article Details
Authors (17)
Patricia Bravo
Medical Parasitology and Infection Biology Swiss Tropical and Public Health Institute Kreuzstrasse 2 Allschwil 4123 Switzerland
Eleonora Diamanti
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)─Helmholtz Centre for Infection Research (HZI) PharmaScienceHub Campus Building E8.1 66123 Saarbrücken Germany
Mostafa M. Hamed
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)─Helmholtz Centre for Infection Research (HZI) PharmaScienceHub Campus Building E8.1 66123 Saarbrücken Germany
Lorenzo Bizzarri
OmicScouts GmbH Lise‐Meitner‐Straße 30 D‐85354 Freising Germany
Natalie Wiedemar
Medical Parasitology and Infection Biology Swiss Tropical and Public Health Institute Kreuzstrasse 2 Allschwil 4123 Switzerland
Armin Passecker
Nicolas M. B. Brancucci
Anna Albisetti
Medical Parasitology and Infection Biology Swiss Tropical and Public Health Institute Kreuzstrasse 2 Allschwil 4123 Switzerland
Christin Gumpp
Boris Illarionov
Hamburg School of Food Science, Institute of Food Chemistry, University of Hamburg 2 , 20146 Hamburg,
Markus Fischer
Matthias Witschel
BASF‐SE Carl‐Bosch‐Strasse 38 67056 Ludwigshafen Germany
Tobias Schehl
BASF‐SE Carl‐Bosch‐Strasse 38 67056 Ludwigshafen Germany
Hannes Hahne
OmicScouts GmbH Lise‐Meitner‐Straße 30 D‐85354 Freising Germany
Pascal Mäser
Matthias Rottmann
Anna K. H. Hirsch
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)─Helmholtz Centre for Infection Research (HZI) PharmaScienceHub Campus Building E8.1 66123 Saarbrücken Germany