School of BioSciences, University of Melbourne, Parkville, Australia.
Elife. 2020 Jul 17;9:e58629. doi: 10.7554/eLife.58629.
The antibiotic actinonin kills malaria parasites () by interfering with apicoplast function. Early evidence suggested that actinonin inhibited prokaryote-like post-translational modification in the apicoplast; mimicking its activity against bacteria. However, Amberg Johnson et al. (2017) identified the metalloprotease FtsH1 as the target of actinonin in the related parasite and implicated FtsH1 as a likely target in malaria parasites. The authors were not, however, able to recover actinonin resistant malaria parasites, leaving the specific target of actinonin uncertain. We generated actinonin resistant by in vitro selection and identified a specific sequence change in FtsH1 associated with resistance. Introduction of this point mutation using CRISPr-Cas9 allelic replacement was sufficient to confer actinonin resistance in . Our data unequivocally identify FtsH1 as the target of actinonin and suggests that actinonin should not be included in the highly valuable collection of 'irresistible' drugs for combatting malaria.
抗生素放线酮通过干扰类质体功能杀死疟原虫。早期的证据表明，放线酮抑制类质体中类似原核生物的翻译后修饰；模仿其对细菌的活性。然而，Amberg Johnson 等人（2017 年）在相关寄生虫中鉴定出金属蛋白酶 FtsH1 是放线酮的靶标，并暗示 FtsH1 可能是疟原虫的靶标。然而，作者无法获得对放线酮具有抗性的疟原虫，使得放线酮的具体靶标不确定。我们通过体外选择生成了对放线酮具有抗性的疟原虫，并鉴定出与抗性相关的 FtsH1 中的特定序列变化。使用 CRISPr-Cas9 等位基因替换引入该点突变足以赋予疟原虫对放线酮的抗性。我们的数据明确将 FtsH1 鉴定为放线酮的靶标，并表明放线酮不应包含在用于对抗疟疾的极具价值的“不可抗拒”药物中。
