Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram-negative Bacteria.
Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram-negative Bacteria.
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DOI：
10.1002/anie.201905230
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发表时间：
2019-06
影响因子：
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通讯作者：
Jiaqing Wang;Deani L. Cooper;Wenjun Zhan;Difei Wu;Hongjian He;Shenghuan Sun;S. Lovett;Bing Xu
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文献类型：
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作者：
Jiaqing Wang;Deani L. Cooper;Wenjun Zhan;Difei Wu;Hongjian He;Shenghuan Sun;S. Lovett;Bing Xu
抗微生物药物耐药性需要新的方法来提高抗生素的功效，特别是针对革兰氏阴性菌。在这里，我们报告了偶联双甘氨酸（GG）抗生素的前药大大加速酯键的细菌内水解，以再生的抗生素对大肠杆菌。杆菌具体地说，GG与氯霉素琥珀酸酯（CLsu）的连接产生了一种新的缀合物（CLsuGG），其对E.杆菌进一步的研究表明，CLsuGG经历细菌内酯酶（例如，BioH和YjfP）在E.杆菌更重要的是，偶联物对骨髓基质细胞的细胞毒性低于CL。CLsuGG的结构类似物表明GG的缀合是加速酯酶催化水解和增强抗生素抗菌效力的有效策略。这项工作，第一次，说明了二肽共轭调节细菌内水解，增加抗生素的疗效和减少药物的不良反应。
Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram-negative bacteria. Here we report that conjugating a diglycine (GG) to a prodrug of antibiotics drastically accelerates intrabacterial hydrolysis of ester bond for regenerating the antibiotics against E. coli. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates a novel conjugate (CLsuGG), which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against E. coli. Further studies reveal that CLsuGG undergoes rapid hydrolysis catalyzed by intrabacterial esterases (e.g., BioH and YjfP) for generating chloramphenicol (CL) in E. coli. More importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells that CL does. The structural analogs of CLsuGG indicate that the conjugation of GG is an effective strategy for accelerating hydrolysis catalyzed by esterases and enhancing antibacterial efficacy of antibiotics. This work, for the first time, illustrates that dipeptide conjugation modulates intrabacterial hydrolysis for increasing antibiotic efficacy and reducing adverse drug effects.