Experimental selection of paromomycin resistance in Leishmania donovani amastigotes induces variable genomic polymorphisms

To evaluate genomic modifications potentially associated with paromomycin (PMM) resistance in Leishmania donovani, twelve experimentally selected clonal lines and the non-cloned preselection population with variable degrees of paromomycin resistance were subjected to whole genome sequencing. Genomic alterations as SNPs, Indels, chromosomal somy and gene copy number variations were compared between the parasite lines. A total of 11 short nucleotide variations, and the copy number alterations in 39 genes were correlated to paromomycin resistance. Some of the identified genes are involved in transcription, translation and protein turn-over, virulence, mitochondrial function, signaling and vesicular trafficking. These results indicate that in Leishmania, the aminoglycoside paromomycin affects protein translational processes and underline the complex and probably multifactorial origin of resistance.