Bhattacharya Arijit, Bigot Sophia, Padmanabhan Prasad Kottayil, Mukherjee Angana, Coelho Adriano, Leprohon Philippe, Papadopoulou Barbara, Ouellette Marc
Dept. of Microbiology, Adamas University, Kolkata, India.
Division of Infectious Disease and Immunity, CHU de Quebec Research Center and Department of Microbiology, Infectious Disease and Immunology, University Laval, Quebec, Canada.
Microb Cell. 2020 Jan 21;7(2):59-61. doi: 10.15698/mic2020.02.708.
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 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 . 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.
寄生虫会引发一系列临床表现，从可自行消退的皮肤损伤到危及生命的疾病。利什曼病的治疗很复杂，部分原因是治疗选择稀缺，还因为对现有药物出现了新出现的或已确立的耐药性。耐药性的一个主要驱动因素是利用寄生虫高度重复的基因组格局扩增耐药基因。全基因组功能获得性筛选的最新出现为研究此类耐药机制注入了新动力，从而鉴定出针对已批准药物（包括锑（SbIII）、米替福新（MIL）、巴龙霉素（PMM）和两性霉素B）的新型耐药因子和药物靶点。然而，这些筛选并未确定单核苷酸变异（SNV），而单核苷酸变异是耐药性的一个重要因素。为了填补这一空白，我们最近的研究描述了化学诱变与下一代测序相结合的优化方法，即一种称为Mut-seq的方法，作为探索具有二倍体到嵌合非整倍体基因组的生物体中耐药基因网络的一种方式。我们的Mut-seq筛选揭示了与脂质代谢相关的基因与对MIL的耐药性之间的关联，并突出了一种蛋白激酶在导致对PMM耐药的翻译过程中的作用。
