In vitro and in vivo activity of solithromycin (CEM-101) against Plasmodium species

Abstract

With the emergence of Plasmodium falciparum infections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potent in vitro activity against the NF54 strain of P. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In an in vivo model of P. berghei infection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promising in vitro and in vivo data support further investigations into the development of solithromycin as an antimalarial agent.

Fig 1

Solithromycin exhibits activity against multidrug-resistant parasites. Two multidrug-resistant parasite lines, Dd2 and 7G8, and azithromycin-resistant clones derived from these parental lines, AZ-R^Dd2 and AZ-R^7G8, were treated with the indicated compounds for 96 h. Solithromycin was significantly more potent than azithromycin for both the sensitive and resistant lines: Dd2, P = 0.004; AZ-R^Dd2, P = 0.007; 7G8, P = 0.0005; and AZ-R^7G8, P = 0.01, all by paired t tests. Azithromycin-resistant parasites were significantly less susceptible to solithromycin than the parental strains (P < 0.05 for both lines), but this effect was only about 50% as great as the effect for azithromycin itself (for Dd2 versus AZ-R^Dd2 there was an 80- and 40-fold shift in potency for azithromycin and solithromycin, respectively; for 7G8 versus AZ-R^7G8 there was a 160- and 70-fold shift in potency for azithromycin and solithromycin, respectively. IC₅₀s (means ± SEM) for each line tested against azithromycin or solithromycin are shown above the individual bars (data were obtained from four independent experiments performed in duplicate).