Sugar-Phosphate Toxicities Attenuate Salmonella Fitness in the Gut.
Sugar-Phosphate Toxicities Attenuate Salmonella Fitness in the Gut.
复制标题
糖磷酸盐毒性会削弱沙门氏菌在肠道中的健康度。
DOI：
10.1128/jb.00344-22
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发表时间：
2022
影响因子：
3.2
通讯作者：
Ahmer,BrianMM
中科院分区：
文献类型：
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作者：
Boulanger,ErinF;Sabag-Daigle,Anice;Baniasad,Maryam;Kokkinias,Katherine;Schwieters,Andrew;Wrighton,KellyC;Wysocki,VickiH;Ahmer,BrianMM
病原体正在以越来越快的速度对抗菌药物产生耐药性，因此需要新的治疗策略。使用沙门氏菌作为模型，我们已经研究了糖-磷酸盐毒性的诱导作为一种潜在的治疗方式。这种方法需要提供一种营养素，同时阻止该营养素的分解，导致有毒中间体的积累。我们假设，这种积累将降低健康的有机体在感染期间的营养供应。我们测试了这一假设，使用突变体缺乏七个基因，其突变预计会导致有毒代谢中间体的积累之一。然后在小鼠胃肠道感染过程中，向ThearaD、galE、rhaD、glpD、mtlD、manA和galT突变体提供适当的糖，无论是在体外还是在体内。除了glpD突变体外，所有突变体都有营养依赖性生长缺陷，提示糖-磷酸盐毒性。在小鼠胃肠道感染期间，5个突变体的适应性下降。在动物的饮用水中提供适当的营养素是引起突变体的适应性缺陷和增强突变体的适应性缺陷所必需的。无论饮用水中提供的营养如何，galE和mtlD突变体都严重衰减。galE的同源物在细菌和人类中广泛存在，使得细菌病原体的特异性靶向变得困难。然而，araD、mtlD和rhaD基因在人类中不存在，在大多数细菌门中似乎是罕见的，并且在肠杆菌科的几个属中是常见的，使得编码的酶成为潜在的窄谱治疗靶点。目前迫切需要确定新的药物靶点和治疗策略。在这项工作中，我们已经组装并表征了我们的模型病原体肠道沙门氏菌中的一系列突变，这些突变以导致有毒糖磷酸盐积累的方式阻断了多种糖利用途径。三个基因中的突变，rhaD，araD，和mtlD，显著降低沙门氏菌在胃肠炎小鼠模型中的适应性，表明RhaD，AraD，和MtlD可能是良好的窄谱药物靶点。糖-磷酸盐毒性的诱导可能是与其他细菌和真菌病原体广泛相关的治疗策略。
Pathogens are becoming resistant to antimicrobials at an increasing rate, and novel therapeutic strategies are needed. Using Salmonella as a model, we have investigated the induction of sugar-phosphate toxicity as a potential therapeutic modality. The approach entails providing a nutrient while blocking the catabolism of that nutrient, resulting in the accumulation of a toxic intermediate. We hypothesize that this build-up will decrease the fitness of the organism during infection given nutrient availability. We tested this hypothesis using mutants lacking one of seven genes whose mutation is expected to cause the accumulation of a toxic metabolic intermediate. ThearaD,galE,rhaD,glpD,mtlD,manA, andgalTmutants were then provided the appropriate sugars, eitherin vitroor during gastrointestinal infection of mice. All but theglpDmutant had nutrient-dependent growth defectsin vitro, suggestive of sugar-phosphate toxicity. During gastrointestinal infection of mice, five mutants had decreased fitness. Providing the appropriate nutrient in the animal’s drinking water was required to cause fitness defects with therhaDandmanAmutants and to enhance the fitness defect of thearaDmutant. ThegalEandmtlDmutants were severely attenuated regardless of the nutrient being provided in the drinking water. Homologs ofgalEare widespread among bacteria and in humans, rendering the specific targeting of bacterial pathogens difficult. However, thearaD,mtlD, andrhaDgenes are not present in humans, appear to be rare in most phyla of bacteria, and are common in several genera ofEnterobacteriaceae, making the encoded enzymes potential narrow-spectrum therapeutic targets.IMPORTANCEBacterial pathogens are becoming increasingly resistant to antibiotics. There is an urgent need to identify novel drug targets and therapeutic strategies. In this work we have assembled and characterized a collection of mutations in our model pathogen, Salmonella enterica, that block a variety of sugar utilization pathways in such a way as to cause the accumulation of a toxic sugar-phosphate. Mutations in three genes,rhaD,araD, andmtlD, dramatically decrease the fitness of Salmonella in a mouse model of gastroenteritis, suggesting that RhaD, AraD, and MtlD may be good narrow-spectrum drug targets. The induction of sugar-phosphate toxicities may be a therapeutic strategy that is broadly relevant to other bacterial and fungal pathogens.