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Deletion of Rv2571c Confers Resistance to Arylamide Compounds in Mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy ( IF 4.9 ) Pub Date : 2021-04-19 , DOI: 10.1128/aac.02334-20
Catherine D Shelton 1 , Matthew B McNeil 1 , Julie V Early 1, 2 , Thomas R Ioerger 3 , Tanya Parish 2, 4
Affiliation  

Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets, and an increased understanding of antibiotic resistance. We have determined the mode of resistance to be a series of arylamide compounds in M. tuberculosis. We isolated M. tuberculosis resistant mutants to two arylamide compounds which are inhibitory to growth under host-relevant conditions (butyrate as a sole carbon source). Thirteen mutants were characterized, and all had mutations in Rv2571c; mutations included a premature stop codon and frameshifts as well as nonsynonymous polymorphisms. We isolated a further 10 strains with mutations in Rv2571c with resistance. Complementation with a wild-type copy of Rv2571c restored arylamide sensitivity. Overexpression of Rv2571c was toxic in both wild-type and mutant backgrounds. We constructed M. tuberculosis strains with an unmarked deletion of the entire Rv2571c gene by homologous recombination and confirmed that these were resistant to the arylamide series. Rv2571c is a member of the aromatic amino acid transport family and has a fusaric acid resistance domain which is associated with compound transport. Since loss or inactivation of Rv2571c leads to resistance, we propose that Rv2571c is involved in the import of arylamide compounds.

中文翻译:

Rv2571c 的缺失赋予结核分枝杆菌对芳基酰胺化合物的抗性

由结核分枝杆菌引起的结核病是一个紧迫的全球健康问题,需要新药、新的药物靶点以及对抗生素耐药性的更多了解。我们确定耐药模式是结核分枝杆菌中的一系列芳基酰胺化合物。我们分离出结核分枝杆菌对两种芳基酰胺化合物的抗性突变体,它们在宿主相关条件下(丁酸盐作为唯一碳源)抑制生长。对 13 个突变体进行了表征,并且都在 Rv2571c 中发生了突变;突变包括过早终止密码子和移码以及非同义多态性。我们分离出另外 10 株具有耐药性的 Rv2571c 突变菌株。与 Rv2571c 的野生型拷贝互补可恢复芳基酰胺敏感性。Rv2571c 的过度表达在野生型和突变体背景下都是有毒的。我们构建了结核分枝杆菌通过同源重组对整个 Rv2571c 基因进行未标记缺失的菌株,并证实这些菌株对芳基酰胺系列具有抗性。Rv2571c 是芳香族氨基酸转运家族的成员,具有与化合物转运相关的镰刀菌酸抗性结构域。由于 Rv2571c 的丢失或失活会导致耐药性,我们建议 Rv2571c 参与芳基酰胺化合物的输入。
更新日期:2021-04-19
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