Loss of Dihydroxyacid Dehydratase Induces Auxotrophy in Bacillus anthracis.
Loss of Dihydroxyacid Dehydratase Induces Auxotrophy in Bacillus anthracis.
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二羟酸脱水酶的丧失会导致炭疽杆菌营养缺陷型。
DOI：
10.1128/jb.00415-21
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发表时间：
2021
影响因子：
3.2
通讯作者：
Maresso,Anthony
中科院分区：
文献类型：
--
作者：
Jelinski,Joseph;Cortez,Madeline;Terwilliger,Austen;Clark,Justin;Maresso,Anthony
炭疽病是由炭疽杆菌感染引起的，如果不及时治疗，可能会导致致命的菌血症和毒血症。目前的感染治疗需要长期服用抗生素。尽管如此，吸入性和胃肠道炭疽仍然会导致致命疾病。通过确定炭疽芽孢杆菌在类宿主环境中生长的关键代谢步骤，可以确定抗菌策略的新目标。在这里，我们报道了ilvD基因，它在合成支链氨基酸的假定途径中编码二羟酸脱水酶，对于炭疽芽孢杆菌在其他限制性微环境中合成异亮氨酸是必需的。我们观察到ΔilvDB。炭疽病不能在缺乏异亮氨酸的培养基中生长，但当添加外源异亮氨酸时，生长会恢复。此外，ΔilvD杆菌不能利用人血红蛋白或血清白蛋白来克服异亮氨酸营养缺陷型，但当提供鼠类形式时可以。这种物种特异性效应是由于人类血红蛋白中缺乏异亮氨酸。此外，即使补充了生理水平的人血清白蛋白、脱铁转铁蛋白、纤维蛋白原和IgG，ilvD敲除菌株相对于未补充的野生型生长也很差。此外，对感染人源化小鼠的比较表明，鼠血红蛋白是 WT 和 ΔilvDbacilli 的异亮氨酸的关键来源。小鼠和人类血液中的进一步生长比较表明，营养缺陷对人类血液的生长有害，而不是小鼠。该报告确定了炭疽芽孢杆菌产生异亮氨酸所必需的 silvDas，并且它在使杆菌在异亮氨酸缺乏的宿主中有效生长方面发挥着关键作用。 重要性 由炭疽芽孢杆菌引起的炭疽病，即使在使用抗生素治疗后，也可引起致命的菌血症和毒血症。该报告鉴定了ilvD基因，该基因编码二羟酸脱水酶，是炭疽芽孢杆菌在营养限制环境（例如其哺乳动物宿主）中合成氨基酸异亮氨酸所必需的。该菌株的使用进一步证明了血红蛋白作为细胞外异亮氨酸的外源来源的独特的物种依赖性利用。通过确定炭疽杆菌在类宿主环境中生长的机制，揭示了治疗干预的新目标。
Anthrax disease is caused by infection with the bacteria Bacillus anthracis which, if left untreated, can result in fatal bacteremia and toxemia. Current treatment for infection requires prolonged administration of antibiotics. Despite this, inhalational and gastrointestinal anthrax still result in lethal disease. By identifying key metabolic steps that B. anthracis uses to grow in host-like environments, new targets for antibacterial strategies can be identified. Here, we report that theilvDgene, which encodes dihydroxyacid dehydratase in the putative pathway for synthesizing branched chain amino acids, is necessary for B. anthracis to synthesize isoleucinede novoin an otherwise limiting microenvironment. We observed that ΔilvDB. anthracis cannot grow in media lacking isoleucine, but growth is restored when exogenous isoleucine is added. In addition,ΔilvDbacilli are unable to utilize human hemoglobin or serum albumin to overcome isoleucine auxotrophy, but can when provided with the murine forms. This species-specific effect is due to the lack of isoleucine in human hemoglobin. Furthermore, even when supplemented with physiological levels of human serum albumin, apotransferrin, fibrinogen, and IgG, theilvDknockout strain grew poorly relative to nonsupplemented wild type. In addition, comparisons upon infecting humanized mice suggest that murine hemoglobin is a key source of isoleucine for both WT and ΔilvDbacilli. Further growth comparisons in murine and human blood show that the auxotrophy is detrimental for growth in human blood, not murine. This report identifiesilvDas necessary for isoleucine production in B. anthracis, and that it plays a key role in allowing the bacilli to effectively grow in isoleucine poor hosts.IMPORTANCEAnthrax disease, caused by B. anthracis, can cause lethal bacteremia and toxemia, even following treatment with antibiotics. This report identifies theilvDgene, which encodes a dihydroxyacid dehydratase, as necessary for B. anthracis to synthesize the amino acid isoleucine in a nutrient-limiting environment, such as its mammalian host. The use of this strain further demonstrated a unique species-dependent utilization of hemoglobin as an exogenous source of extracellular isoleucine. By identifying mechanisms that B. anthracis uses to grow in host-like environments, new targets for therapeutic intervention are revealed.