Beyond One Gene: a systematic review of layered evidence for antileishmanial resistance in Leishmania infantum.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.