Herbicidal properties of antimalarial drugs

Abstract

The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules.

Figure 1. Quantification of plant growth.

To quantify growth within a plate using ImageJ, an original image (i) was filtered using the ‘Threshold Colour’ plug-in so that only the shades of green are retained (ii) before the image was converted to an 8-bit image (iii) and threshold adjusted to convert grey shades into red pixels that are measurable by ImageJ (iv). In this way, from an image, the green pixels can be counted and a value for total area in mm² obtained.

Figure 2. Growth of A. thaliana on media containing herbicides and antimalarials.

A. thaliana was raised from seeds on growth media containing 20 μg/mL of antimalarials and antibiotics (top row, middle row) in comparison to negative controls (DMSO, water) and known herbicides (bottom row). To test light and solution instability, media was pre-treated at 22 °C with light for 1 week (+light) or left at 4 °C in the dark for 1 week (+dark/cold) before sowing seeds. For each compound and condition, three replicates were done and a representative image is shown.

Figure 3. Potency of herbicidal antimalarials.

(A) A. thaliana seeds raised on a concentration gradient of herbicides, antimalarials, and antibiotics. (B) Dose-response curves for all compounds, except DMSO. The X-axis is a log scale with concentrations tested. The Y-axis is given as percentage growth inhibition compared to DMSO control. Each data point is a mean value from six replicates (details in Supplementary Table 2). (◆) Ciprofloxacin, (■) atrazine, (△) asulam, (×) sulfadiazine, (×) sulfadoxine, (◯) clindamycin, (✚) glufosinate ammonium, (▬) artesunate, (▭) cycloguani, (◇) DHA, (□) glyphosate, and (▲) pyrimethamine. (C) LD₅₀ (μg/mL) measured for all compounds.

Figure 4. Physicochemical properties of antimalarial compounds versus herbicides.

Representative charts (A–C) were extracted using an interactive database containing the physicochemical properties of 334 commercial herbicides. New data points (i.e. compounds studied here) were added to the database and plotted on graphs comparing two chemical properties, (A) molar mass vs lipophilicity (Log P), (B) molar mass vs aqueous solubility (Log S), (C) distribution coefficient (Log D) vs polar surface area (Ų) and (D) molar mass vs polar surface area (Ų). Cluster analyses show the general trends into which the antimalarial compounds fall. Black dots represent the antimalarial compounds that significantly inhibited plant growth, whereas solid grey dots represent antimalarial compounds with poor or no herbicidal activity. Transparent dots represent the 334 herbicidal compounds of the original database.