The human pathogens Plasmodium and Schistosoma are each responsible for over 200 million infections annually, being particularly problematic in low- and middle-income countries. There is a pressing need for new drug targets for these diseases, driven by emergence of drug-resistance in Plasmodium and the overall dearth of new drug targets for Schistosoma. Here, we explored the opportunity for pathogen-hopping by evaluating a series of quinoxaline-based anti-schistosomal compounds for activity against P. falciparum. We identified compounds with low nanomolar potency against 3D7 and multidrug-resistant strains. Evolution of resistance using a mutator P. falciparum line revealed a low propensity for resistance. Only one of the series, compound 22, yielded resistance mutations, including point mutations in a non-essential putative hydrolase pfqrp1, as well as copy-number amplification of a phospholipid-translocating ATPase, pfatp2, a potential target. Notably, independently generated CRISPR-edited mutants in pfqrp1 also showed resistance to compound 22 and a related analogue. Moreover, previous lines with pfatp2 copy-number variations were similarly less susceptible to challenge with the new compounds. Finally, we examined whether the predicted hydrolase activity of PfQRP1 underlies its mechanism of resistance, showing that both mutation of the putative catalytic triad and a more severe loss of function mutation elicited resistance. Collectively, we describe a compound series with potent activity against two important pathogens and their potential target in P. falciparum.

Biological Chemistry and Drug Discovery Wellcome Centre for Anti Infectives Research University of Dundee Dundee United Kingdom

Center for Malaria Therapeutics and Antimicrobial Resistance Division of Infectious Diseases Department of Medicine Columbia University Irving Medical Center New York New York United States

Department of Life Sciences Aberystwyth University Aberystwyth United Kingdom

Department of Microbiology and Immunology Columbia University Irving Medical Center New York New York United States

Department of Organic Chemistry UCT Prague Prague Czech Republic

Swansea University Medical School Swansea United Kingdom

Wellcome Sanger Institute Wellcome Genome Campus Hinxton United Kingdom

PLoS Pathog. 2025 Feb 03;21(2):e1012216. doi: 10.1371/journal.ppat.1012216. PubMed

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