Exploring antimicrobial resistance in Leishmania donovani through systems biology insights – A review

Leishmaniasis, a protozoan disease affecting tropical and subtropical regions, poses significant treatment challenges due to antimicrobial resistance. Traditional therapies for leishmaniasis include pentavalent antimonial, amphotericin B, miltefosine, pentamidine, and paromomycin, each with unique mechanisms, such as disrupting pathways for trypanothione metabolism, DNA, RNA, and phospholipid synthesis, the mitochondrial membrane potential, and inducing apoptosis. These therapies have started failing due to toxicity and microbial resistance. Such resistance in Leishmania involves complex mechanisms, including gene amplification, point mutations, and efflux pump overexpression, that have been studied using methods such as in vitro susceptibility testing and molecular techniques. While traditional methods have provided a critical foundation for understanding resistance, they often face challenges in capturing the full systemic complexity of the underlying mechanisms. In these circumstances, systems biology approaches offer promising solutions as powerful complement to traditional experimentation by integrating diverse data types from genomics, transcriptomics, and proteomics along with bioinformatics tools to construct comprehensive models of parasite function and drug response. This holistic perspective improves the identification of resistance mechanisms, reveals interrelated biological networks, and uncovers novel drug targets. In this comprehensive review, we discuss the mechanisms underlying antimicrobial resistance development in Leishmania donovani and the application of systems biology approaches to its exploration. The review aims to explore the future possibilities for evidence-based treatment decisions, guide future research, and ultimately enhance Leishmaniasis management and control worldwide.