A Shared Adaptive Backbone and Divergent Routes of Experimentally Selected Drug Resistance in Leishmania

Drug resistance remains a major challenge to antileishmanial chemotherapy, but whether distinct selection pressures converge on shared adaptive programs or generate drug-specific states remains unclear. We generated seven drug-selected derivatives from a common laboratory-adapted Leishmania sp. parental line using niclosamide, crizotinib, lapatinib, epirubicin, mitotane, idarubicin, and fingolimod, and profiled parental and selected lines by RNA sequencing in biological triplicate. Replicate transcriptomes were highly reproducible. NIC-R, CRI-R, LAP-R, MIT-R, and FIN-R shared a broad resistance-associated core of 407 upregulated and 746 downregulated genes. CRI-R and LAP-R showed strong convergence, sharing 582 upregulated and 926 downregulated genes, whereas EPI-R and IDA-R shared only five upregulated and six downregulated genes despite selection by related anthracyclines. IDA-R showed a focal chromosome 34 RNA-abundance increase encompassing LDBPK_341060/P-glycoprotein; EPI-R showed a histone-rich signature and chromosome 12 negative RNA-abundance pattern; and FIN-R/MIT-R displayed opposing chromosome 23/32 signals. Direction-specific enrichment further distinguished line-specific functional programs involving translation/ribosome, metabolic/energy, chromatin, proteostasis, and transporter-related processes. Overall, the data resolved a hierarchical resistance architecture comprising a shared five-line transcript-abundance backbone, strong CRI-R/LAP-R convergence, marked EPI-R/IDA-R divergence, and superimposed focal or chromosome-biased RNA-dosage candidate signals. These findings indicate that chemically diverse pressures can drive Leishmania into resistance-associated states through both reusable and drug-specific adaptive routes, while the DNA level and functional validation remain necessary to establish causal mechanisms.