title: Assessment of drug resistance related genes as candidate markers for treatment outcome prediction of cutaneous leishmaniasis in Brazil.
abstract: The great public health problem posed by leishmaniasis has substantially worsened in recent years by the emergence of clinical failure. In Brazil, the poor prognosis observed for patients infected by Leishmania braziliensis (Lb) or L. guyanensis (Lg) may be related to parasite drug resistance. In the present study, 19 Lb and 29 Lg isolates were obtained from infected patients with different treatment outcomes. Translated amino acid sequence polymorphisms from four described antimony resistance related genes (AQP1, hsp70, MRPA and TRYR) were tested as candidate markers for antimonial treatment failure prediction. Possibly due to the low intraspecific variability observed in Lg samples, none of the prediction models had good prognosis values. Most strikingly, one mutation (T579A) found in hsp70 of Lb samples could predict 75% of the antimonial treatment failure clinical cases. Moreover, a multiple logistic regression model showed that the change from adenine to guanine at position 1735 of the hsp70 gene, which is responsible for the T579A mutation, significantly increased the chance of Lb clinical isolates to be associated with treatment failure (OR=7.29; CI 95%=[1.17, 45.25]; p=0.0331). The use of molecular markers to predict treatment outcome presents practical and economic advantages as it allows the development of rapid assays to monitor the emergence of drug resistant parasites that can be clinically applied to aid the prognosis of cutaneous leishmaniasis in Brazil.
authors: Laboratório de Pesquisa em Leishmaniose/Coleção de Leishmania do Instituto Oswaldo Cruz (IOC) - Fiocruz, Rio de Janeiro, Brazil.
authors: Davi Coe
authors: DC
authors: Torres
authors: Marcelo
authors: M
authors: Ribeiro-Alves
authors: Gustavo A S
authors: GA
authors: Romero
authors: Alberto M R
authors: AM
authors: Dávila
authors: Elisa
authors: E
authors: Cupolillo
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D001938:Brazil; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007892:Leishmania braziliensis / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D018334:Leishmania guyanensis / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D007897:Leishmaniasis, Mucocutaneous / Q000188:drug therapy / Q000473:pathology; D008536:Meglumine / Q000494:pharmacology / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D008969:Molecular Sequence Data; D009154:Mutation; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D015800:Protozoan Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D005819:Genetic Markers; D018840:HSP70 Heat-Shock Proteins; D009942:Organometallic Compounds; D015800:Protozoan Proteins; D008536:Meglumine; D000077485:Meglumine Antimoniate