Pseudomonas aeruginosa is 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-resistant Pseudomonas strains 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 isolated Pseudomonas strains 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 with P. aeruginosa strain PAO1 infection. These data suggest that polycarboxylation by DTPA conjugation is an effective approach to enhance antipseudomonal activity of aminopenicillins.

中文翻译：

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通过氨基青霉素的多羧化开发有效的抗假单胞菌 β-内酰胺

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（如重症监护病房的患者）构成严重风险。耐多药假单胞菌的出现菌株增加了对新的抗假单胞菌药物的需求。本研究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-脲基青霉素杂化物，并评估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，不仅针对实验室菌株 PAO1，还针对临床分离的假单胞菌对哌拉西林和羧苄青霉素耐药的菌株。DTPA-Amox对培养的哺乳动物细胞没有明显的细胞毒作用。此外，在白细胞减少症的体内模型中，DTPA-Amox 治疗对铜绿假单胞菌PAO1 株感染小鼠的存活产生了适度但具有统计学意义的改善。这些数据表明通过 DTPA 缀合进行的多羧化是增强氨基青霉素抗假单胞菌活性的有效方法。