Antimony resistance in Leishmania guyanensis

Drug resistance remains a major threat on leishmaniasis chemotherapy. Using next generation sequencing, we produced the whole-genome of four independent Leishmania guyanensis antimony-resistant (SbR) mutants and found different chromosomal alterations including aneuploidy, gene amplification and gene deletion. The amplification of the gene coding for multidrug resistance associated protein A occurred in the four mutants in the absence of extrachromosomal elements and most likely results from intrachromosomal duplication. For three out of the four mutants, antimony resistance was mainly explained by the deletion of part of the subtelomeric region of chromosome 31 harboring the gene coding for the aquaglyceroporin 1 (LgAQP1). We also describe for the first time the selection of a single point mutation in LgAQP1 (G133D) by antimony pressure and functionality confirmed its role in resistance through drug sensitivity and antimony accumulation assays.