Polymyxins are considered a last-line treatment against infections caused by multidrug-resistant (MDR) Gram-negative bacteria. In addition to their use as a potent antibiotic, polymyxins have also been utilized as outer membrane (OM) permeabilizers, capable of augmenting the activity of a partner antibiotic. Several polymyxin derivatives have been developed accordingly, with the objective of mitigating associated nephrotoxicity. The conversion of polymyxins to guanidinylated derivatives, whereby the L-γ-diaminobutyric acid (Dab) amines are substituted with guanidines, are described herein. The resulting guanidinylated colistin and polymyxin B (PMB) exhibited reduced antibacterial activity but preserved OM permeabilizing properties that allowed potentiation of several antibiotic classes. Rifampicin, erythromycin, ceftazidime and aztreonam were particularly potentiated against clinically relevant MDR Gram-negative bacteria. The potentiating effects of guanidinylated polymyxins with ceftazidime or aztreonam were further enhanced by adding the β-lactamase inhibitor avibactam.

中文翻译：

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胍基化多粘菌素作为外膜透化剂能够增强利福平、红霉素、头孢他啶和氨曲南对革兰氏阴性菌的抵抗力

多粘菌素被认为是对抗多重耐药 (MDR) 革兰氏阴性菌感染的最后一线治疗方法。除了用作强效抗生素外，多粘菌素还被用作外膜 (OM) 透化剂，能够增强伴侣抗生素的活性。相应地开发了几种多粘菌素衍生物，目的是减轻相关的肾毒性。本文描述了多粘菌素向胍基化衍生物的转化，其中 L-γ-二氨基丁酸 (Dab) 胺被胍取代。由此产生的胍基化多粘菌素和多粘菌素 B (PMB) 表现出降低的抗菌活性，但保留了 OM 通透特性，允许增强几种抗生素类别。利福平、红霉素、头孢他啶和氨曲南对临床相关的 MDR 革兰氏阴性菌特别有效。添加 β-内酰胺酶抑制剂 avibactam 可进一步增强胍基化多粘菌素与头孢他啶或氨曲南的增强作用。