Parasitology Department, Medical Faculty, Centre for Infectious Diseases, University Hospital Heidelberg, Heidelberg University, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
Sci Rep. 2024 Aug 27;14(1):19821. doi: 10.1038/s41598-024-70713-y.
Malaria remains one of the highest causes of morbidity and mortality, with 249 million cases and over 608,000 deaths in 2022. Insecticides, which target the Anopheles mosquito vector, are the primary method to control malaria. The widespread nature of resistance to the most important insecticide class, the pyrethroids, threatens the control of this disease. To reverse the stall in malaria control there is urgent need for new vector control tools, which necessitates understanding the molecular basis of pyrethroid resistance. In this study we utilised multi-omics data to identify uridine-diphosphate (UDP)-glycosyltransferases (UGTs) potentially involved in resistance across multiple Anopheles species. Phylogenetic analysis identifies sequence similarities between Anopheline UGTs and those involved in agricultural pesticide resistance to pyrethroids, pyrroles and spinosyns. Expression of five UGTs was characterised in An. gambiae and An. coluzzii to determine constitutive over-expression, induction, and tissue specificity. Furthermore, a UGT inhibitor, sulfinpyrazone, restored susceptibility to pyrethroids and DDT in An. gambiae, An. coluzzii, An. arabiensis and An. funestus, the major African malaria vectors. Taken together, this study provides clear association of UGTs with pyrethroid resistance as well as highlighting the potential use of sulfinpyrazone as a novel synergist for vector control.
疟疾仍然是发病率和死亡率最高的疾病之一，2022 年有 2.49 亿例病例和超过 60.8 万人死亡。杀虫剂是控制疟疾的主要方法，针对疟蚊传播媒介。广泛存在的对最重要的杀虫剂类别的抗药性，即拟除虫菊酯，威胁着这种疾病的控制。为了扭转疟疾控制的僵局，迫切需要新的病媒控制工具，这就需要了解拟除虫菊酯抗性的分子基础。在这项研究中，我们利用多组学数据来鉴定可能参与多种按蚊物种抗性的尿苷二磷酸（UDP）-糖基转移酶（UGTs）。系统发育分析确定了按蚊 UGTs 与参与农业中拟除虫菊酯、吡咯和多杀菌素抗性的 UGTs 之间的序列相似性。在冈比亚按蚊和库蚊中对 5 个 UGTs 的表达进行了特征描述，以确定其组成型过表达、诱导和组织特异性。此外，UGT 抑制剂磺胺嘧啶在冈比亚按蚊、库蚊、阿巴辛按蚊和致倦库蚊中恢复了对拟除虫菊酯和滴滴涕的敏感性，这些都是主要的非洲疟疾媒介。总之，这项研究清楚地表明 UGTs 与拟除虫菊酯抗性有关，并强调了磺胺嘧啶作为一种新型病媒控制增效剂的潜在用途。
