Abstract
Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg−1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.
Highlights
Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens
AN3661 was active at nanomolar concentrations against P. falciparum laboratory strains known to be sensitive (3D7) or resistant (W2, Dd2, K1, HB3, FCR3 and TM90C2B) to standard antimalarial drugs, and it was active in ex vivo studies of fresh Ugandan field isolates (Fig. 1b and Supplementary Table 1)
Subsequent studies showed AN3661 to be active at low nanomolar concentrations against multiple P. falciparum strains that vary in their susceptibility to standard antimalarials and to be highly effective when administered orally to treat P. berghei and P. falciparum infections in mice
Summary
Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratoryadapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg À 1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf[3], which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). Benzoxaboroles are boron-containing compounds that have shown potent activity against a wide range of infectious pathogens, including bacteria[5,6], fungi[7] and protozoans[8,9,10,11,12]. Crisaborole, a PDE4 inhibitor, has completed phase 3 clinical trials for atopic dermatitis This manuscript reports the antimalarial profile and mechanism of action of another benzoxaborole, AN3661, which was a HO. AN3661 demonstrated potent antimalarial activity, and genetic and biochemical studies identified its target as a homologue of mammalian cleavage and polyadenylation specificity factor (CPSF) subunit 3
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