A Research Agenda for Malaria Eradication: Drugs

bMalaria's ability to rapidly adapt to new drugs has allowed it to remain one of the most devastating infectious diseases of humans. Understanding and tracking the genetic basis of these adaptations are critical to the success of treatment and intervention strategies. The novel antimalarial resistance locus PF10_0355 (Pfmspdbl2) was previously associated with the parasite response to halofantrine, and functional validation confirmed that overexpression of this gene lowered parasite sensitivity to both halofantrine and the structurally related antimalarials mefloquine and lumefantrine, predominantly through copy number variation. Here we further characterize the role of Pfmspdbl2 in mediating the antimalarial drug response of Plasmodium falciparum. Knockout of Pfmspdbl2 increased parasite sensitivity to halofantrine, mefloquine, and lumefantrine but not to unrelated antimalarials, further suggesting that this gene mediates the parasite response to a specific class of antimalarial drugs. A single nucleotide polymorphism encoding a C591S mutation within Pfmspdbl2 had the strongest association with halofantrine sensitivity and showed a high derived allele frequency among Senegalese parasites. Transgenic parasites expressing the ancestral Pfmspdbl2 allele were more sensitive to halofantrine and structurally related antimalarials than were parasites expressing the derived allele, revealing an allele-specific effect on drug sensitivity in the absence of copy number effects. Finally, growth competition experiments showed that under drug pressure, parasites expressing the derived allele of Pfmspdbl2 outcompeted parasites expressing the ancestral allele within a few generations. Together, these experiments demonstrate that modulation of Pfmspdbl2 affects malaria parasite responses to antimalarial drugs. Malaria drug resistance poses a serious threat to treatment and control efforts (1, 2). Loci such as pfcrt, dhfr, and pfmdr1 are all known to play a role in mediating Plasmodium falciparum drug resistance and can do so through mutations or copy number variation (CNV) (3), but the precise mechanisms of resistance to many antimalarial drugs are poorly understood. Additionally, these well-known loci do not fully explain the range of responses observed in resistant parasites, suggesting that other loci may be involved in mediating parasite drug sensitivity (4, 5).Pfmspdbl2, also called PF10_0355, PF3D7_1036300, and MSP3.8, is a novel antimalarial resistance locus recently identified in a genome-wide association study (GWAS) of 50 global parasite isolates with a high-density single nucleotide polymorphism (SNP) array (6). CNV was also observed at this locus among natural parasite isolates, and parasites with more than one copy of Pfmspdbl2 tended to be more resistant to halofantrine. Overexpression of either the sensitive or the resistant allele of Pfmspdbl2 made parasites less sensitive to halofantrine, mefloquine, and lumefantrine but not to structurally unrelated antimalarials. This validated Pfmspdbl2 as a novel antimalaria...

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confidence: 99%

Modulation of PF10_0355 (MSPDBL2) Alters Plasmodium falciparum Response to Antimalarial Drugs

Tyne

Uboldi

Healer

et al. 2013

“…From the perspective of future malaria elimination and eradication, leading experts of the scientific malaria community and the World Health Organization have defined a research agenda for the development of next-generation antimalarial medicines (1,15,16). Given the complex task of developing drugs against malaria parasites, the scientific malaria community has provided several robust in vitro methodologies and frameworks in order to standardize drug development in academic research (1,(17)(18)(19)(20)(21).…”

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confidence: 99%

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.M alaria remains one of the most severe infectious diseases that disproportionately affects the public health and economic welfare of the world's poorest communities. The causative agents of malaria are protozoan parasites of the genus Plasmodium. Among the five Plasmodium species that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), P. falciparum is the most virulent and is responsible for severe clinical outcomes and most of the deaths associated with malaria. Until the development of an effective vaccine, chemotherapy remains a major frontline strategy for the control and possible future elimination of malaria. The emergence and rapid spread of drug-resistant parasites undermine efforts at reducing the global disease burden and emphasize the need for drugs with novel chemical entities that exploit new molecular targets while overcoming established drug resistance mechanisms. Ideally, such drugs should quickly kill the pathogenic asexual blood stages of P. falciparum and, in addition, be effective against other developmental stages, in particular the sexual stages that transmit the infection from the human to the mosquito host (1, 2).Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in v...

“…ffective chemotherapy remains a critical component of current malaria control strategies and is essential to treat severe malaria (1). The introduction of artemisinin combination therapies (ACTs) has successfully lowered malaria mortality but does not effectively control the spread of the disease, because ACTs do not eliminate the sexual stages of the parasite that are required for malaria transmission (2,3).…”

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confidence: 99%

Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen

Tanaka

Guiguemde

Barnett

et al. 2015

c Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gameto- cytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria.