Selecting Tambjamine Resistance in Plasmodium falciparum

Malaria is a life-threatening disease caused by Plasmodium parasites, with P. falciparum being the most lethal. Multi-drug resistant parasites are emerging at an increasing rate, making the need for novel antimalarials greater than ever. Tambjamines, a natural alkaloid product isolated from bacteria and marine invertebrates, have been semi-synthesized into novel, potent antimalarial compounds. Tambjamines have shown promising in vitro activity against P. falciparum, however, their molecular target is still unknown. Resistance selection is a process in which a microorganism is subjected to increasing concentrations of a growth-inhibiting drug to acquire an inheritable mutation that allows the microorganism to multiply even in high concentrations of drug. We hypothesized that producing tambjamine-resistant P. falciparum parasites would result in one or more mutations in the DNA sequence of those resistant lines, revealing the molecular target(s) of the tambjamines. Over the course of one year, the chloroquine-resistant Dd2 strain of P. falciparum was cultured in vitro and exposed to continuous pressure of fully synthetic tambjamine analog KAR457, using concentrations up to 50 nM. After approximately 1 year of drug pressure, growth inhibition assays were performed. The control flask showed an IC50 value of 26.5 nM and a drugged flask showed an IC50 value of 28.1 nM for KAR457, showing little to no indication of resistance. It is possible that tambjamines have multiple or nonspecific targets when inhibiting the growth of P. falciparum parasites. Due to inconclusive results, future studies require a change in method such as increasing the amount of parasites under drug pressure to increase the likelihood of selecting resistance, pressuring parasites at higher concentrations for a longer duration, and using different strains of P. falciparum. Inability to select drug resistance in a laboratory setting may indicate difficulty selecting resistance in vivo, showing promise for KAR457 as an effective novel antimalarial for humans