Repositioning Antibiotics Against Plasmodium falciparum RAD5 and WD11 as Novel Antimalarial Targets

Area of Science:

• Parasitology
• Drug Discovery
• Computational Biology

Background:

• Artemisinin resistance in Plasmodium falciparum poses a significant threat to malaria control.
• PfRAD5 and PfWD11 proteins are implicated in parasite survival and drug resistance.
• The therapeutic potential of targeting PfRAD5 and PfWD11 remains largely unexplored.

Purpose of the Study:

• To evaluate PfRAD5 and PfWD11 as novel antimalarial drug targets.
• To screen existing antibiotics for activity against these targets.
• To assess the efficacy of drug combinations for malaria treatment.

Main Methods:

• Integrated computational (AlphaFold, molecular docking, molecular dynamics) and experimental (in vitro assays, qPCR) approaches.
• Screened a library of 216 antibiotics against Plasmodium falciparum.
• Tested top-ranked compounds and combinations in P. falciparum 3D7 cultures.

Main Results:

• Identified strong binders to PfRAD5 (talampicillin, dicloxacillin, raltegravir) and PfWD11 (puromycin).
• Puromycin demonstrated significant in vitro inhibition (85% at 100 μg/mL).
• Triple combination (puromycin + raltegravir + dicloxacillin) achieved complete inhibition; synergistic effects observed with puromycin + chloroquine.

Conclusions:

• PfRAD5 and PfWD11 are validated as novel antimalarial targets.
• Repurposed antibiotics, particularly puromycin in synergistic combinations, represent a viable strategy against resistant malaria strains.
• This approach offers a cost-effective means to accelerate antimalarial drug development.