Abstract
There is great concern regarding the rapid emergence and spread of drug-resistance in Plasmodium falciparum, the parasite responsible for the most severe form of human malaria. Parasite populations resistant to some or all the currently available antimalarial treatments are present in different world regions. Considering the need for novel and integrated approaches to control malaria, combinations of drugs were tested on P. falciparum. The primary focus was on doxycycline, an antibiotic that specifically targets the apicoplast of the parasite. In combination with doxycycline, three different drugs known to inhibit efflux pumps (verapamil, elacridar and ivermectin) were tested, with the assumption that they could increase the intracellular concentration of the antibiotic and consequently its efficacy against P. falciparum. We emphasize that elacridar is a third-generation ABC transporters inhibitor, never tested before on malaria parasites. In vitro experiments were performed on asexual stages of two strains of P. falciparum, chloroquine-sensitive (D10) and chloroquine-resistant (W2). Incubation times on asynchronous or synchronous cultures were 72h or 96h, respectively. The antiplasmodial effect (i.e. the IC50) was determined by measuring the activity of the parasite lactate dehydrogenase, while the interaction between drugs was determined through combination index (CI) analyses. Elacridar achieved an IC50 concentration comparable to that of ivermectin, approx. 10-fold lower than that of verapamil, the other tested ABC transporter inhibitor. CI results showed synergistic effect of verapamil plus doxycycline, which is coherent with the starting hypothesis, i.e. that ABC transporters represent potential targets, worth of further investigations, towards the development of companion molecules useful to enhance the efficacy of antimalarial drugs. At the same time, the observed antagonistic effect of doxycycline in combination with ivermectin or elacridar highlighted the importance of drug testing, to avoid the de-facto generation of a sub-dosage, a condition that facilitates the development of drug resistance.
Highlights
Despite the efforts to eradicate malaria, the disease is still one of the major causes of death in low-income countries, with over 200 million cases in 2018, and about half a million deaths
After 72h of incubation, no significant differences were found between the two strains of P. falciparum in terms of susceptibility to ivermectin, doxycycline or elacridar (Fig 1A–1C)
Inadequate funding [1, 45], climate changes [46, 47], resistance of malaria vectors towards the most commonly used classes of insecticides [4, 5], and the continuous emergence of parasite resistance towards antimalarial drugs [6, 48], are all factors that might be responsible for the recent increase in malaria incidence
Summary
Despite the efforts to eradicate malaria, the disease is still one of the major causes of death in low-income countries, with over 200 million cases in 2018, and about half a million deaths. In the last few years, the trend of malaria decrease has levelled off, with a slight worrisome increase in malaria cases in the period 2015–2017 [1]. This recent increase in malaria incidence can be attributed to many social and economic factors, and to the development of multiple resistances of the parasites to antimalarial drugs [2, 3], and of the vectors towards insecticides [4, 5]. Since 2001, WHO recommends artemisinin-based combination therapies (ACTs) as first-line intervention in almost all countries where malaria is endemic [9], but resistance to ACT is emerging [10]. The armamentarium of effective antimalarials is quite limited, and the search for novel companion drugs to be used in antimalarial combination therapy is a critical need
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