A niclosamide–tobramycin hybrid adjuvant potentiates cefiderocol against P. aeruginosa?

RSC Medicinal Chemistry Pub Date: 2021-07-27 DOI: 10.1039/D1MD00206F

Abstract

There is an urgent need for new therapies to overcome antimicrobial resistance (AMR) especially against Gram-negative bacilli (GNB). Multicomponent therapy combining antibiotics with enhancer molecules known as adjuvants is an emerging strategy to combat AMR. We have previously reported tobramycin-based adjuvants which are able to potentiate various antibiotics. In order to expand the repertoire of tobramycin hybrid adjuvants, a new hybrid containing niclosamide, an FDA approved anthelmintic which has recently demonstrated a variety of interesting biological effects, was synthesized. It was found that this conjugate can potentiate several antibiotics against multidrug-resistant GNB, including the recently approved siderophore cephalosporin cefiderocol. 8 μg ml?1 of the niclosamide–tobramycin hybrid in combination therapy against a pandrug-resistant strain of P. aeruginosa was able to lower the cefiderocol MIC 32-fold, from 8 μg ml?1 to 0.25 μg ml?1 in iron-rich media where siderophore uptake is reduced. These results indicate that a niclosamide–tobramycin hybrid adjuvant can serve to potentiate a newly approved antibiotic.

Graphical abstract: A niclosamide–tobramycin hybrid adjuvant potentiates cefiderocol against P. aeruginosa
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