Novel niclosamide-derived adjuvants elevating the efficacy of polymyxin B against MDR Pseudomonas aeruginosa DK2

Pseudomonas aeruginosa (P. aeruginosa) DK2 is a multidrug-resistant (MDR) gram-negative bacterial pathogen, being observed serious resistance to the 'last-resort' antibiotic, polymyxin B (PB). Combination therapies with adjuvants have emerged as effective strategies to reactivate the antibiotics resisted by MDR bacteria. Herein, we screened a library of approved drugs and found that niclosamide (NIC), an anthelmintic drug, could potentiate the efficacy of PB against MDR P. aeruginosa DK2. Next, a series of novel NIC-derived adjuvants were designed, synthesized, and evaluated the synergistic activity with PB. Among them, the combination of 15 with PB displayed superior elimination of P. aeruginosa DK2 in vitro and in vivo compared with the single administration. Moreover, this combination decelerated PB-resistance progress in DK2, along with lower potential toxicity. Overall, this study provides a strategy for development antibiotic adjuvants to potentiate PB against MDR P. aeruginosa infections. (C) 2022 Elsevier Masson SAS. All rights reserved.

Automated summary

This study screened a library of drugs and found that the anthelmintic drug niclosamide (NIC) could enhance the efficacy of polymyxin B (PB) against multidrug-resistant Pseudomonas aeruginosa. Novel NIC-derived adjuvants were designed and synthesized, and one of them (adjuvant 15) exhibited synergistic activity with PB, effectively eliminating P. aeruginosa DK2 and slowing down the development of PB resistance.