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

Taotao Lu; Xinyu Zheng; Fei Mao; Qiao Cao; Qin Cao; Jin Zhu; Xiaokang Li; Lefu Lan; Baoli Li; Jian Li

doi:10.1016/j.ejmech.2022.114318

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

Eur J Med Chem. 2022 Jun 5:236:114318. doi: 10.1016/j.ejmech.2022.114318. Epub 2022 Mar 25.

Authors

Taotao Lu¹, Xinyu Zheng¹, Fei Mao¹, Qiao Cao², Qin Cao², Jin Zhu¹, Xiaokang Li¹, Lefu Lan³, Baoli Li⁴, Jian Li⁵

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: llan@simm.ac.cn.
⁴ Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou, 570228, Hainan, China. Electronic address: libaolilibaoli@163.com.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou, 570228, Hainan, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali, 671000, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China. Electronic address: jianli@ecust.edu.cn.

PMID: 35398731
DOI: 10.1016/j.ejmech.2022.114318

Abstract

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.

Keywords: Adjuvants; Drug repurposing; Niclosamide; Polymyxin B; Pseudomonas aeruginosa DK2.

MeSH terms

Anti-Bacterial Agents* / pharmacology
Drug Resistance, Multiple, Bacterial
Microbial Sensitivity Tests
Niclosamide* / pharmacology
Polymyxin B* / pharmacology
Pseudomonas aeruginosa* / drug effects

Substances

Anti-Bacterial Agents
Niclosamide
Polymyxin B