Cysteine hydropersulfide inactivates β-lactam antibiotics to form ring opened carbothioic S-acids in bacteria.
Cysteine hydropersulfide inactivates β-lactam antibiotics to form ring opened carbothioic S-acids in bacteria.
复制标题
半胱氨酸氢过硫化物使β-内酰胺抗生素失活，在细菌中形成开环的硫代硫酸。
DOI：
10.1021/acschembio.1c00027
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
T.
中科院分区：
文献类型：
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作者：
Ono;K.;Kitamura;Y.;Zhang;T.;Tsutsuki;H.;Rahman;A.;Akaike;T.;Ihara;T.;Sawa;T.
在细菌硫代谢过程中形成的硫化氢（H2S）与细菌对抗菌剂的内在耐药性的发展有关。尽管H2S转化为过硫化物大大增强了H2S的生物化学性质，如抗氧化活性，但过硫化物对抗生素耐药性的影响仍然未知。本文研究了H2S单独或与胱氨酸形成过硫化半胱氨酸（CysSSH）对抗菌剂活性的影响。通过使用纸片扩散试验，我们发现CysSSH处理有效地灭活了青霉素类（青霉素G和氨苄青霉素）和碳青霉烯类（美罗培南）的β-内酰胺。这些β-内酰胺对单独使用H2S或单独使用胱氨酸的处理具有抗性。相比之下，头孢菌素类β-内酰胺类药物（头孢克洛和头孢哌酮）和非β-内酰胺类抗生素（四环素、卡那霉素、红霉素和氧氟沙星）在CysSSH治疗后保持稳定。色谱和质谱分析表明，CysSSH可直接与β-内酰胺反应生成β-内酰胺开环硫代羧酸（BL-COSH）。此外，我们证明了某些细菌（例如，大肠杆菌（Escherichia coli）和金黄色葡萄球菌（Staphylococcus aureus）能有效降解β-内酰胺类抗生素，形成BL-COSH，并将其转运至胞外。这些数据表明，CysSSH介导的β-内酰胺分解可能有助于细菌对β-内酰胺类的内在耐药性。BL-COSH可能成为CysSSH介导的β-内酰胺类抗生素耐药性的生物标志物，并可用于研究潜在的抗菌佐剂，通过减少细菌中的过硫化物来增强β-内酰胺类抗生素的抗菌活性。
Hydrogen sulfide (H2S) formed during sulfur metabolism in bacteria has been implicated in the development of intrinsic resistance to antibacterial agents. Despite the conversion of H2S to hydropersulfides greatly enhancing the biochemical properties of H2S such as antioxidant activity, the effects of hydropersulfides on antibiotic resistance have remained unknown. In this work, we investigated the effects of H2S alone or together with cystine to form cysteine hydropersulfide (CysSSH) on the activities of antibacterial agents. By using the disc diffusion test, we found that CysSSH treatment effectively inactivated β-lactams of the penicillin class (penicillin G and ampicillin) and the carbapenem class (meropenem). These β-lactams were resistant to treatment with H2S alone or cystine alone. In contrast, cephalosporin class β-lactams (cefaclor and cefoperazone) and non-β-lactam antibiotics (tetracycline, kanamycin, erythromycin, and ofloxacin) were stable after CysSSH treatment. Chromatographic and mass spectrometric analyses revealed that CysSSH directly reacted with β-lactams to form β-lactam ring-opened carbothioic S-acids (BL-COSH). Furthermore, we demonstrated that certain bacteria (e.g.,Escherichia coliandStaphylococcus aureus) efficiently decomposed β-lactam antibiotics to form BL-COSH, which were transported to the extracellular space. These data suggest that CysSSH-mediated β-lactam decomposition may contribute to intrinsic bacterial resistance to β-lactams. BL-COSH may become useful biomarkers for CysSSH-mediated β-lactam resistance and for investigation of potential antibacterial adjuvants that can enhance the antibacterial activity of β-lactams by reducing the hydropersulfides in bacteria.