Development of potent antipseudomonal β‐lactams by means of polycarboxylation of aminopenicillins
Development of potent antipseudomonal β‐lactams by means of polycarboxylation of aminopenicillins
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通过氨基青霉素多羧化作用开发强效抗假单胞菌β-内酰胺类药物
DOI：
10.1111/1348-0421.12930
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发表时间：
2021
影响因子：
2.6
通讯作者：
Sawa Tomohiro
中科院分区：
文献类型：
--
作者：
Akter Shahinur;Migiyama Yohei;Tsutsuki Hiroyasu;Ono Katsuhiko;Hamasaki Chika;Zhang Tianli;Miyao Kenki;Toyomoto Touya;Yamamoto Keiichi;Islam Waliul;Sakagami Takuro;Matsui Hirotaka;Yamaguchi Yoshihiro;Sawa Tomohiro
铜绿假单胞菌是一种革兰氏阴性机会性病原体，对免疫抑制个体和其他极其脆弱的患者（如重症监护室患者）构成严重风险。多重耐药假单胞菌菌株的出现增加了对新的抗假单胞菌药物的需求。在这项研究中，合成了一系列氨基修饰的氨基青霉素衍生物，它们具有不同数量的羧基，结构类似于羧基青霉素-脲基青霉素杂合体，并评价了它们的抗假单胞菌活性。在合成的衍生物中，二亚乙基三胺五乙酸（DTPA）修饰的阿莫西林（DTPA-Amox）显示出有效的抗假单胞菌活性，不仅对实验室菌株PAO 1，而且对临床分离的对哌拉西林和羧苄西林耐药的假单胞菌菌株。DTPA‐Amox对培养的哺乳动物细胞无明显细胞毒性作用。此外，在体内白细胞减少症模型中，DTPA-Amox治疗对P.产气荚膜梭菌PAO 1感染。这些数据表明，通过DTPA缀合的多羧基化是增强氨基青霉素抗假单胞菌活性的有效途径。
Pseudomonas aeruginosais a Gram‐negative opportunistic pathogen that presents a serious risk to immunosuppressed individuals and other extremely vulnerable patients such as those in intensive care units. The emergence of multidrug‐resistantPseudomonasstrains has increased the need for new antipseudomonal agents. In this study, a series of amino group‐modified aminopenicillin derivatives was synthesized that have different numbers of carboxyl groups and structurally resemble carboxypenicillin–ureidopenicillin hybrids, and their antipseudomonal activities were evaluated. Among the derivatives synthesized, diethylenetriaminepentaacetic acid (DTPA)‐modified amoxicillin (DTPA‐Amox) showed potent antipseudomonal activity, not only against the laboratory strain PAO1 but also against clinically isolatedPseudomonasstrains that were resistant to piperacillin and carbenicillin. DTPA‐Amox had no obvious cytotoxic effects on cultured mammalian cells. In addition, in an in vivo model of leukopenia, DTPA‐Amox treatment produced a moderate but statistically significant improvement in the survival of mice withP. aeruginosastrain PAO1 infection. These data suggest that polycarboxylation by DTPA conjugation is an effective approach to enhance antipseudomonal activity of aminopenicillins.
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