Antileishmanial drug resistance in Leishmania infantum is a major challenge for visceral leishmaniasis control, yet the genetic evidence remains fragmented across functional, genomic, structural and expression-based studies. This systematic review mapped parasite genes and loci associated with resistance, altered drug susceptibility, therapeutic failure or relapse.
A PRISMA 2020-compliant systematic review was conducted using PubMed, SciELO and VHL/LILACS, with searches updated before manuscript finalization. Eligible studies evaluated Leishmania infantum genetic or locus-level evidence linked to antileishmanial susceptibility or clinically anchored outcomes. Gene-drug associations were synthesized without meta-analysis and stratified into three evidence layers: functional validation with phenotype, genomic or structural association, and expression-based association.
Twenty-nine studies were included. Evidence was concentrated in a limited number of therapeutic axes, mainly antimonials, miltefosine, amphotericin B and allopurinol. The most consistently supported evidence axes included the MT/ROS3 miltefosine transport axis, MRPA-associated antimony resistance, NUC1/NUC2 within the miltefosine sensitivity locus, and loci linked to redox, sequestration, sterol and lipid remodeling. Structural evidence highlighted MSL deletion as a clinically anchored structural association with miltefosine treatment failure or relapse and reduced METK copy number as an allopurinol-associated signal in canine isolates. Expression-based studies showed heterogeneous profiles, especially for antimony-related uptake and thiol/redox pathways.
Altered drug susceptibility in L. infantum is best explained by layered, stage-dependent and context-sensitive genetic modules rather than a single universal resistance marker. This evidence-graded synthesis supports cautious prioritization of candidate loci for prospective validation and informs the design of molecular surveillance studies within a One Health framework.
}, year = {2026}, journal = {Infection, Genetics and Evolution}, volume = {144}, pages = {1 - 17}, month = {10/2026}, publisher = {Elsevier BV}, issn = {1567-1348}, url = {https://www.sciencedirect.com/science/article/pii/S1567134826001292/pdfft?md5=ac526f100a1c79ea0c3f86a67e9f522e&pid=1-s2.0-S1567134826001292-main.pdf}, doi = {10.1016/j.meegid.2026.106005}, language = {ENG}, }