Targeting Polyamine Metabolism in Human Intracellular Pathogens Colonizing Macrophages—Connecting the Dots Between Mycobacterium, Leishmania and Plasmodium

Polyamine metabolism has emerged as an important determinant of pathogen survival, proliferation, and persistence, highlighting polyamine-associated proteins and metabolic pathways as promising therapeutic targets. This is particularly relevant to major infectious diseases, including tuberculosis, malaria, leishmaniasis, and trypanosomiasis, in which pathogens exploit and remodel host cellular processes to evade immune responses and establish intracellular survival. Increasing evidence indicates that alterations in host–pathogen polyamine metabolism contribute to pathogen adaptation and persistence, providing opportunities for therapeutic intervention. Over the past decade, several components of polyamine biosynthesis, transport, and utilization have been identified and validated as potential drug targets in clinically relevant pathogens. Concurrently, advances in medicinal chemistry have led to the development of polyamine-derived compounds with enhanced specificity toward pathogen-associated polyamine proteins and metabolic pathways. These findings have strengthened the rationale for target-based drug discovery as a complementary strategy to conventional antimicrobial development, particularly in the context of the increasing prevalence of multidrug-resistant pathogens. In this review, we summarize recent advances in the identification and validation of polyamine-related drug targets in pathogens responsible for tuberculosis, malaria, leishmaniasis, and trypanosomiasis. We further discuss emerging strategies for the design and optimization of polyamine-derived therapeutic compounds, with emphasis on their molecular targets, mechanisms of action, and potential for overcoming antimicrobial resistance. Finally, we highlight current challenges and future opportunities for exploiting polyamine metabolism in the development of next-generation therapeutics against these major infectious diseases.