In vivo evaluation of genetic and pharmacological targeting of the Leshmania donovani polyamine biosynthetic pathway

Leishmania parasites cause leishmaniasis, a neglected tropical disease with limited treatment options and no effective vaccine. Current drugs are toxic, costly, and face resistance, highlighting the need for new targets. This study investigates the polyamine biosynthetic pathway in Leishmania, which differs significantly from mammalian hosts. Using targeted gene replacement, we generated null mutants for four key enzymes (ARG, ODC, SPDSYN, ADOMETDC), confirming the pathway’s essential role in parasite survival and infectivity. Oral supplementation and pharmacologic inhibition demonstrated that polyamine metabolism can be nutritionally or chemically targeted, supporting its potential as a therapeutic strategy against leishmaniasis.