New insights in the mode of action of anti-leishmanial drugs by using chemical mutagenesis screens coupled to next-generation sequencing
Authors:Arijit Bhattacharya1, Sophia Bigot2, Prasad Kottayil Padmanabhan2, Angana Mukherjee2, Adriano Coelho3, Philippe Leprohon2, Barbara Papadopoulou2 and Marc Ouellette2
doi: 10.15698/mic2020.02.708
Volume 7, pp. 59 to 61, published 21/01/2020.
1 Dept. of Microbiology, Adamas University, Kolkata, India.
2 Division of Infectious Disease and Immunity, CHU de Quebec Research Center and Department of Microbiology, Infectious Disease and Immunology, University Laval, Quebec, Canada.
3 Institute of Biology, University of Campinas, Campinas, Brazil.
Keywords:
Mut-seq, chemical mutagenesis, resistance, miltefosine, paromomycin, Leishmania
Corresponding Author(s):
Conflict of interest statement:
The authors have no conflict of interest to declare.
Please cite this article as:
Arijit Bhattacharya, Sophia Bigot, Prasad Kottayil Padmanabhan, Angana Mukherjee, Adriano Coelho, Philippe Leprohon, Barbara Papadopoulou and Marc Ouellette (2020). New insights in the mode of action of anti-leishmanial drugs by using chemical mutagenesis screens coupled to next-generation sequencing. Microbial Cell 7(2): 59-61. doi: 10.15698/mic2020.02.708
© 2020 Bhattacharya et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which al-lows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Leishmania parasites are responsible for a range of clinical manifestations ranging from self-resolving cutaneous sores to life-threatening diseases. The management of leishmaniasis is complicated in part by the scarcity of treatment options but also by the emerging or established resistance to available drugs. A major driver of resistance in Leishmania is the amplification of resistance genes taking advantage of the highly repetitive genomic landscape of the parasite. The recent advent of whole genome gain of function screens gave new momentum to the study of such resistance mechanisms, leading to the identification of novel resistance factors and drug targets against approved drugs, which include antimony (SbIII), miltefosine (MIL), paromomycin (PMM), and amphotericin B. However, these screens do not pinpoint single nucleotide variations (SNVs), an important contributor of drug resistance. To fill the gap, our recent study describes the optimization of chemical mutagenesis coupled to next generation sequencing, an approach called Mut-seq, as a way to explore networks of drug resistance genes in organisms with a diploid to mosaic aneuploid genome like Leishmania. Our Mut-seq screen revealed associations between genes linked with lipid metabolism and resistance to MIL, and highlighted the role of a protein kinase in translation leading to resistance to PMM.