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

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.