A niclosamide–tobramycin hybrid adjuvant potentiates cefiderocol againstP. aeruginosa

RSC Medicinal Chemistry
2021.0

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<sup>-1</sup> of the niclosamide-tobramycin hybrid in combination therapy against a pandrug-resistant strain of <i>P. aeruginosa</i> was able to lower the cefiderocol MIC 32-fold, from 8 μg ml<sup>-1</sup> to 0.25 μg ml<sup>-1</sup> 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.

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