Ramirez Danzel Marie, Ramirez Danyel, Arthur Gilbert, Zhanel George, Schweizer Frank
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0W2, Canada.
Antibiotics (Basel). 2022 Sep 20;11(10):1277. doi: 10.3390/antibiotics11101277.
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.
多粘菌素被认为是治疗多重耐药（MDR）革兰氏阴性菌感染的最后一道防线。除了用作强效抗生素外，多粘菌素还被用作外膜（OM）通透剂，能够增强联合抗生素的活性。相应地，已经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，即将L-γ-二氨基丁酸（Dab）胺用胍取代。所得的胍基化粘菌素和多粘菌素B（PMB）抗菌活性降低，但保留了外膜通透特性，可增强几种抗生素类别的活性。利福平、红霉素、头孢他啶和氨曲南对临床相关的多重耐药革兰氏阴性菌尤其有增效作用。加入β-内酰胺酶抑制剂阿维巴坦可进一步增强胍基化多粘菌素与头孢他啶或氨曲南的增效作用。
