Identification of metabolic pathways essential for fitness of Salmonella Typhimurium in vivo.
Identification of metabolic pathways essential for fitness of Salmonella Typhimurium in vivo.
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鉴定体内沙门氏菌鼠伤寒必不可少的代谢途径。
DOI：
10.1371/journal.pone.0101869
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Olsen JE
中科院分区：
文献类型：
--
作者：
Jelsbak L;Hartman H;Schroll C;Rosenkrantz JT;Lemire S;Wallrodt I;Thomsen LE;Poolman M;Kilstrup M;Jensen PR;Olsen JE
细菌感染仍然是全球人类和动物健康的威胁，迫切需要找到新的干预目标。在目前的研究中，我们使用了一个计算机模型的代谢网络沙门氏菌肠血清型鼠伤寒沙门氏菌，并确定了对反应（割集）预测需要在体内生长。我们称这种切割集为合成营养缺陷型对。我们通过分析选定的单突变体和双突变体在系统性小鼠感染中的表现，测试了这些突变体是否会揭示新抗生素的可能组合靶点。确定了102个切割集。其中63个仅包括由完全注释的基因编码的途径，并且从这个子集中，我们选择了涉及氨基酸或多胺生物合成的五个切割集。一个切割集（asnA/asnB）在体外和体内都显示了冗余，表明天冬酰胺是S.感染过程中的鼠伤寒。trpB/trpA以及单突变体在体外生长时被减毒，而只有双突变体在体内是切割组，这强调了先前的观察结果，即色氨酸对于成功的感染结果是必需的。speB/speF，speC在体外不受影响，但在感染过程中减弱，表明多胺是必不可少的毒力显然在一个生长独立的方式。发现serA/glyA切割集如模型所预测的生长减弱。然而，不仅双突变体，而且glyA突变体，被发现是减毒的毒力。这将甘氨酸的产生或甘氨酸转化为THF添加到感染期间的基本反应列表中。一对（thrC/kbl）在体外显示真正的冗余，但在体内不显示，表明苏氨酸在感染期间可用于细菌。这些数据增加了对宿主内环境中可用营养素的现有知识，并确定了抗生素可能的新靶点。
Bacterial infections remain a threat to human and animal health worldwide, and there is an urgent need to find novel targets for intervention. In the current study we used a computer model of the metabolic network of Salmonella enterica serovar Typhimurium and identified pairs of reactions (cut sets) predicted to be required for growth in vivo. We termed such cut sets synthetic auxotrophic pairs. We tested whether these would reveal possible combined targets for new antibiotics by analyzing the performance of selected single and double mutants in systemic mouse infections. One hundred and two cut sets were identified. Sixty-three of these included only pathways encoded by fully annotated genes, and from this sub-set we selected five cut sets involved in amino acid or polyamine biosynthesis. One cut set (asnA/asnB) demonstrated redundancy in vitro and in vivo and showed that asparagine is essential for S. Typhimurium during infection. trpB/trpA as well as single mutants were attenuated for growth in vitro, while only the double mutant was a cut set in vivo, underlining previous observations that tryptophan is essential for successful outcome of infection. speB/speF,speC was not affected in vitro but was attenuated during infection showing that polyamines are essential for virulence apparently in a growth independent manner. The serA/glyA cut-set was found to be growth attenuated as predicted by the model. However, not only the double mutant, but also the glyA mutant, were found to be attenuated for virulence. This adds glycine production or conversion of glycine to THF to the list of essential reactions during infection. One pair (thrC/kbl) showed true redundancy in vitro but not in vivo demonstrating that threonine is available to the bacterium during infection. These data add to the existing knowledge of available nutrients in the intra-host environment, and have identified possible new targets for antibiotics.
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影响因子：
3.7
作者：
Jelsbak L;Thomsen LE;Wallrodt I;Jensen PR;Olsen JE
通讯作者：
Olsen JE
影响因子：
4.2
作者：
Fürst, P;Stehle, P
通讯作者：
Stehle, P
影响因子：
3.2
作者：
CHEN, J;BREVET, A;PLATEAU, P
通讯作者：
PLATEAU, P
DOI：
10.1073/pnas.012363899
发表时间：
2002-01-08
影响因子：
11.1
作者：
Chico-Calero, I;Suárez, M;Vázquez-Boland, JA
通讯作者：
Vázquez-Boland, JA
影响因子：
3.1
作者：
Cersini, A;Salvia, AM;Bernardini, ML
通讯作者：
Bernardini, ML