Ricardo Vieira da Costa, Marcelo Cerilo-Filho, Maria Naely Gomes Almeida, Amanda Almeida Silva, Marrara Pereira Sampaio, Andréa Regina de Souza Baptista, Ricardo Scher, Tatiana Rodrigues de Moura, Ricardo Luiz Dantas Machado
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.
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.