Dual Effects of Feed-Additive-Derived Chelerythrine in Combating Mobile Colistin Resistance
Huangwei Song,
Xueyang Wang,
Muchen Zhang,
Zhiyu Zou,
Siyuan Yang,
Tian Yi,
Jianfeng Wang,
Dejun Liu,
Yingbo Shen,
Chongshan Dai,
Zhihai Liu,
Timothy R. Walsh,
Jianzhong Shen,
Congming Wu,
Yang Wang
Affiliations
Huangwei Song
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Xueyang Wang
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Muchen Zhang
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Zhiyu Zou
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Siyuan Yang
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Tian Yi
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Jianfeng Wang
State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130015, China
Dejun Liu
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Yingbo Shen
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Chongshan Dai
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Zhihai Liu
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
Timothy R. Walsh
Ineos-Oxford Institute of Antimicrobial Research, Department of Biology, University of Oxford, Oxford OX1 3SZ, UK
Jianzhong Shen
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
Congming Wu
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China; Corresponding authors.
Yang Wang
National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China; Corresponding authors.
The emergence and spread of the mobile colistin-resistance gene, mcr-1, and its variants pose a challenge to the use of colistin, a last-resort antibiotic used to treat severe infections caused by extensively drug-resistant (XDR) Gram-negative pathogens. Antibiotic adjuvants are a promising strategy to enhance the efficacy of colistin against colistin-resistant pathogens; however, few studies have considered the effects of adjuvants on limiting resistance-gene transmission. We found that chelerythrine (4 mg∙L−1) derived from Macleaya cordata extract, which is used as an animal feed additive, reduced the minimal inhibitory concentration (MIC) of colistin against an mcr-1 positive Escherichia coli (E. coli) strain by 16-fold (from 2.000 to 0.125 mg∙L−1), eliminated approximately 104 colony-forming units (CFUs) of an mcr-1-carrying strain in a murine intestinal infection model, and inhibited the conjugation of an mcr-1-bearing plasmid in vitro (by > 100-fold) and in a mouse model (by up to 5-fold). A detailed analysis revealed that chelerythrine binds to phospholipids on bacterial membranes and increases cytoplasmic membrane fluidity, thereby impairing respiration, disrupting proton motive force (PMF), generating reactive oxygen species (ROS), and decreasing intracellular adenosine triphosphate (ATP) levels, which subsequently downregulates mcr-1 and conjugation-associated genes. These dual effects of chelerythrine can expand the use of antibiotic adjuvants and may provide a new strategy for circumventing mobile colistin resistance.
