Bisamidine derivatives as candidates for tegumentary leishmaniasis therapy: phenotypic screening in infection of macrophages and mechanistic insights with dual RNA-seq
Leishmania braziliensis is the primary causative agent of American tegumentary leishmaniasis, a critical parasitic tropical neglected disease. The chemotherapeutic arsenal has limited efficacy and significant toxic effects that lead to the urgent need to develop new medicines. Using the drug repurposing approach, histone-modifying enzyme inhibitors have been the subject of developing new drugs against neglected parasitic diseases. In this work, furamidine, a diphenyl furan inhibitor of human Protein Arginine Methyltransferase (PRMT), as well as a library of 31 developed analogs, were tested against L. braziliensis in the in vitro infection of macrophages. The action of the most active and selective compound, BSF2 (EC 50 of 0.64 uM, SI of 19.76), was investigated by dual RNA-Seq in the in vitro infection of macrophages assay at 0.16 uM BSF2. The dual-transcriptome revealed a modest effect on parasite transcription. Changes detected in L. braziliensis following BSF2 treatment were related to ubiquitination, chromatin remodelling, and peroxisomal membrane transport pathways. In addition, it had a significant effect on regulating the host macrophage transcriptome, including the downregulation of TNF, IL-17, NF-KappaB, and Toll-like receptor pathways. This work opens new venues for developing new chemotherapy for leishmaniasis based on BSF2 or derivatives and highlights the dual-transcriptome as a valuable phenotypic assay tool to investigate host-parasite interactions for antileishmanial drug discovery.