NOVEL CLASS OF ANTI-MALARIAL COMPOUNDS: IN VITRO NEGATIVE SELECTION TO REDUCE POTENTIAL SIDE EFFECTS IN HUMANS

Malaria threatens nearly 40% of the world's population, and new compounds are urgently needed due to increasing drug resistance to the current antimalarials. One promising potential target is the methylerythritol phosphate (MEP) pathway, located in the apicoplast. This pathway is used to synthesize isoprenoids which are essential for survival of the malaria parasite and is absent in the human host. However, microorganisms within the human gut possess this pathway, and are necessary to the host. Ideally, any new antimalarials developed will kill the malaria parasite without affecting the microflora of the human gut, thus reducing or eliminating drug-induced side effects. Our laboratory had identified a new potential antimalarial lead that may target the MEP pathway. Several analogs have been synthesized to improve parasiticidal activity and lower off-target toxicity. In order to address potential toxicity to the human gut microflora, E. coli was used as a representative organism. Several potential antimalarial compounds were screened for inhibition of E. coli. Preliminary results show that all four new compounds that were effective against the lethal strain of malaria parasite did not inhibit E. coli growth under aerobic conditions.