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 multidrugresistant 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.

Antiapicoplast and Gametocytocidal Screening To Identify the Mechanisms of Action of Compounds within the Malaria Box

“…Interestingly, we noted that the mechanism of action of MMV008138 is more like that of FOS than that of DOX. In general, drugs like DOX, which target apicoplast genome replication, transcription, protein translation, posttranslation modification, or protein turnover, exhibit a delayed-death phenotype (9)(10)(11)(12)(13)(14)(15). The kinetics of MMV008138 provided circumstantial support for the hypothesis that this drug acts more directly on the metabolism of the organelle than through interference with its biogenesis.…”

“…Several antibiotics, such as doxycycline (DOX), azithromycin, solithromycin, chloramphenicol, and clindamycin, kill malaria parasites by interfering with apicoplast genome replication, transcription, protein translation, posttranslation modification, or protein turnover (9)(10)(11)(12)(13)(14). Parasites treated with these antibiotics initially present normal morphology and continue to grow and release daughter cells (merozoites) that are capable of invading new host cells.…”

Pharmacochemical Aspects of the Evolution from Erythromycin to Neomacrolides, Ketolides and Neoketolides

“…This chemical variation, coupled with the replacement of the imidazole-pyridine couple of Telithromycin by a 1,2,3-trizolyl-aniline, led to the development of Solithromycin (Figure 8). Solithromycin or CEM-101 actually presented better chemical stability, better affinity for the 50S subunit of the bacterial ribosome by the creation of a third interaction site [133]- [138]. It does not inhibit nicotinic acetylcholine receptors nAChRs like Telithromycin, so should not have the harmful side effects of Telithromycin [135].…”

Several Human Cyclin-Dependent Kinase Inhibitors, Structurally Related to Roscovitine, As New Anti-Malarial Agents

“…As a consequence of the resistance, an alarming resurgence of malaria has occurred, and the anti-malarial drug space should be urgently extended. New targets, such as the apicoplast [5], the protozoan proteases [6], or the specific mitochondrial electron transport chain are currently being investigated [7]. Protein kinases, which regulate protozoan growth and differentiation during its life cycle, have also emerged to be among the most promising new anti-malarial targets [8,9,10,11].…”