Impact of Antibiotics with Various Target Sites on the Metabolome of Staphylococcus aureus
Impact of Antibiotics with Various Target Sites on the Metabolome of Staphylococcus aureus
复制标题
DOI：
10.1128/aac.03104-14
复制
发表时间：
2014-12-01
影响因子：
4.9
通讯作者：
Lalk, Michael
中科院分区：
文献类型：
--
作者：
Doerries, Kirsten;Schlueter, Rabea;Lalk, Michael
在这项研究中，利用全球内和细胞外代谢谱来研究具有不同细胞靶点的抗生素化合物对金黄色葡萄球菌HG 001代谢组的影响。初级代谢主要包括，但不常见的葡萄球菌代谢产物中检测到的胞质溶胶S。金黄色葡萄球菌，包括景天庚酮糖-1，7-二磷酸和具有丙氨酸-丝氨酰残基的UDP-MurNAc-五肽。通过以时间依赖性方式比较未应激和应激葡萄球菌细胞的代谢谱，我们发现代谢组内的广泛影响。对于每种抗生素化合物，检测到代谢物的积累和消耗，通常包括整个生物合成途径，如中心碳和氨基酸代谢以及肽聚糖、嘌呤和嘧啶合成。环丙沙星改变（脱氧）核苷酸池以及肽聚糖前体，从而将停滞的DNA和细胞壁合成联系起来。红霉素往往会增加磷酸戊糖途径和赖氨酸中间产物的数量。磷霉素抑制肽聚糖合成的第一个酶促步骤，随后肽聚糖前体水平降低，但底物水平升高，如UDP-GlcNAc和丙氨酸-丙氨酸。相比之下，万古霉素和氨苄青霉素抑制外细胞表面上的肽聚糖构建的最后阶段。因此，UDP-MurNAc-肽的量急剧增加，导致隔区的形态学改变和中心代谢物水平的总体降低。此外，每种抗生素影响三羧酸循环中间体的细胞内水平。
In this study, global intra-and extracellular metabolic profiles were exploited to investigate the impact of antibiotic compounds with different cellular targets on the metabolome of Staphylococcus aureus HG001. Primary metabolism was largely covered, yet uncommon staphylococcal metabolites were detected in the cytosol of S. aureus, including sedoheptulose-1,7-bisphosphate and the UDP-MurNAc-pentapeptide with an alanine-seryl residue. By comparing the metabolic profiles of unstressed and stressed staphylococcal cells in a time-dependent manner, we found far-ranging effects within the metabolome. For each antibiotic compound, accumulation as well as depletion of metabolites was detected, often comprising whole biosynthetic pathways, such as central carbon and amino acid metabolism and peptidoglycan, purine, and pyrimidine synthesis. Ciprofloxacin altered the pool of (deoxy)nucleotides as well as peptidoglycan precursors, thus linking stalled DNA and cell wall synthesis. Erythromycin tended to increase the amounts of intermediates of the pentose phosphate pathway and lysine. Fosfomycin inhibited the first enzymatic step of peptidoglycan synthesis, which was followed by decreased levels of peptidoglycan precursors but enhanced levels of substrates such as UDP-GlcNAc and alanine-alanine. In contrast, vancomycin and ampicillin inhibited the last stage of peptidoglycan construction on the outer cell surface. As a result, the amounts of UDP-MurNAc-peptides drastically increased, resulting in morphological alterations in the septal region and in an overall decrease in central metabolite levels. Moreover, each antibiotic affected intracellular levels of tricarboxylic acid cycle intermediates.