Guanidinylated Polymyxins as Outer Membrane Permeabilizers Capable of Potentiating Rifampicin, Erythromycin, Ceftazidime and Aztreonam against Gram-Negative Bacteria

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-gamma-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 beta-lactamase inhibitor avibactam.

Automated summary

Polymyxins are effective as a last resort treatment for infections caused by multidrug-resistant Gram-negative bacteria. In addition to being potent antibiotics, polymyxins can enhance the activity of partner antibiotics by permeabilizing the outer membrane. By converting polymyxins to guanidinylated derivatives, their antibacterial activity is reduced but their outer membrane permeabilizing properties are preserved, resulting in potentiation of several antibiotic classes. The addition of the beta-lactamase inhibitor avibactam further enhances the potentiating effects of guanidinylated polymyxins when combined with ceftazidime or aztreonam.