应对可转移多黏菌素耐药性——饲料添加剂来源的白屈菜红碱具有双重效应

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

工程（英文） ›› 2024, Vol. 32 ›› Issue (1) : 163-173.

PDF(2234 KB)
PDF(2234 KB)
工程（英文） ›› 2024, Vol. 32 ›› Issue (1) : 163-173. DOI: 10.1016/j.eng.2023.06.012
研究论文
Article

应对可转移多黏菌素耐药性——饲料添加剂来源的白屈菜红碱具有双重效应

作者信息 +

Dual Effects of Feed-Additive-Derived Chelerythrine in Combating Mobile Colistin Resistance

Author information +
History +

摘要

可转移多黏菌素耐药基因mcr-1及其变异体的出现、蔓延严重威胁了多黏菌素作为临床治疗多重耐药革兰阴性菌感染最后一道防线药物的药效。寻找抗生素佐剂是恢复多黏菌素对其耐药菌敏感性的有效策略。然而，鲜有研究探索抗生素佐剂对多黏菌素耐药基因传播的影响。本研究发现，来源于饲料添加剂博落回散中的白屈菜红碱（4 mg∙L−1）在体外抑菌试验能使多黏菌素对mcr-1阳性大肠杆菌的MIC降低16倍（由 2 至 0.125 mg∙L−1），且在肠道感染模型中与对照组相比，能降低104左右的mcr-1阳性大肠杆菌菌载量。同时，白屈菜红碱在体外试验中能降低mcr-1阳性质粒的接合转移频率（超过100倍），且在体内肠道接合转移模型中能显著降低该质粒的接合转移频率（5倍）。机制研究发现，白屈菜红碱通过靶向细菌细胞膜上的磷脂成分，增大细胞膜的流动性，抑制了细菌呼吸作用，扰乱质子动势（proton motive force, PMF），产生活性氧（reactive oxygen species, ROS），造成细菌胞内ATP耗竭，下调了mcr-1及接合转移相关基因的转录水平，从而实现既能增强多黏菌素对抗耐药菌作用，又能抑制耐药质粒接合转移的双重作用。白屈菜红碱的双重作用拓展了抗生素佐剂的应用范围，并提供了应对多黏菌素耐药的新思路。

Abstract

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.

关键词

白屈菜红碱 / 抗生素佐剂 / 接合转移抑制剂 / 多黏菌素 / 双重作用 /

Keywords

Chelerythrine / Antibiotic adjuvant / Conjugation inhibitor / Colistin / mcr-1 / Dual effects

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用
Huangwei Song, Xueyang Wang, Muchen Zhang. 应对可转移多黏菌素耐药性——饲料添加剂来源的白屈菜红碱具有双重效应. Engineering. 2024, 32(1): 163-173 https://doi.org/10.1016/j.eng.2023.06.012

参考文献

原文顺序 | 文献年度倒序 | 文中引用次数倒序
[1]
J. Li, R.L. Nation, J.D. Turnidge, R.W. Milne, K. Coulthard, C.R. Rayner, et al.. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis, 6 (9) ( 2006), pp. 589-601
[2]
Y. Wang, C. Xu, R. Zhang, Y. Chen, Y. Shen, F. Hu, et al.. Changes in colistin resistance and mcr-1 abundance in Escherichia coli of animal and human origins following the ban of colistin-positive additives in China: an epidemiological comparative study. Lancet Infect Dis, 20 (10) ( 2020), pp. 1161-1171
[3]
Y. Liu, Y. Wang, T.R. Walsh, L. Yi, R. Zhang, J. Spencer, et al.. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis, 16 (2) ( 2016), pp. 161-168
[4]
Z. Ling, W. Yin, Z. Shen, Y. Wang, J. Shen, T.R. Walsh. Epidemiology of mobile colistin resistance genes mcr-1 to mcr-9. J Antimicrob Chemother, 75 (11) ( 2020), pp. 3087-3095
[5]
F.F. Andrade, D. Silva, A. Rodrigues, C. Pina-Vaz.Colistin update on its mechanism of action and resistance, present and future challenges. Microorganisms, 8 (11) ( 2020), p. 1716
[6]
J. Sun, H. Zhang, Y. Liu, Y. Feng. Towards understanding MCR-like colistin resistance. Trends Microbiol, 26 (9) ( 2018), pp. 794-808
[7]
X. Xiao, F. Zeng, R. Li, Y. Liu, Z. Wang.Subinhibitory concentration of colistin promotes the conjugation frequencies of mcr-1- and bla NDM-5-positive plasmids. Microbiol Spectr, 10 (2) ( 2022), p. e02160-21
[8]
S.A. McEwen, P.J. Collignon. Antimicrobial resistance: a one health perspective. Microbiol Spectr, 6 (2) (2018), Article ARBA-0009-2017
[9]
S. Hernando-Amado, T.M. Coque, F. Baquero, J.L. Martínez. Defining and combating antibiotic resistance from one health and global health perspectives. Nat Microbiol, 4 (9) ( 2019), pp. 1432-1442
[10]
Y. Wang, G.B. Tian, R. Zhang, Y. Shen, J.M. Tyrrell, X. Huang, et al.. Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study. Lancet Infect Dis, 17 (4) ( 2017), pp. 390-399
[11]
K. Outterson, J.H. Powers, G.W. Daniel, M.B. McClellan. Repairing the broken market for antibiotic innovation. Health Aff, 34 (2) ( 2015), pp. 277-285
[12]
D.J. Payne, L.F. Miller, D. Findlay, J. Anderson, L. Marks.Time for a change: addressing R&D and commercialization challenges for antibacterials. Philos Trans R Soc Lond B Biol Sci, 370 (1670) ( 2015), p. 20140086
[13]
G.D. Wright. Opportunities for natural products in 21st century antibiotic discovery. Nat Prod Rep, 34 (7) ( 2017), pp. 694-701
[14]
M. Tyers, G.D. Wright. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat Rev Microbiol, 17 (3) ( 2019), pp. 141-155
[15]
C.R. MacNair, J.M. Stokes, L.A. Carfrae, A.A. Fiebig-Comyn, B.K. Coombes, M.R. Mulvey, et al.. Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics. Nat Commun, 9 ( 2018), p. 458
[16]
Y. Liu, R. Li, X. Xiao, Z. Wang. Antibiotic adjuvants: an alternative approach to overcome multi-drug resistant Gram-negative bacteria. Crit Rev Microbiol, 45 (3) ( 2019), pp. 301-314
[17]
G.D. Wright. Antibiotic adjuvants: rescuing antibiotics from resistance. Trends Microbiol, 24 (11) ( 2016), pp. 862-871
[18]
M.G. Moloney. Natural products as a source for novel antibiotics. Trends Pharmacol Sci, 37 (8) ( 2016), pp. 689-701
[19]
O. Genilloud. Natural products discovery and potential for new antibiotics. Curr Opin Microbiol, 51 ( 2019), pp. 81-87
[20]
M. Song, Y. Liu, T. Li, X. Liu, Z. Hao, S. Ding, et al.. Plant natural flavonoids against multidrug resistant pathogens. Adv Sci, 8 (15) ( 2021), Article e2100749
[21]
Y. Zhou, S. Liu, T. Wang, H. Li, S. Tang, J. Wang, et al.. Pterostilbene, a potential MCR-1 inhibitor that enhances the efficacy of polymyxin B. Antimicrob Agents Chemother, 62 (4) ( 2018), p. e02146-17
[22]
R. Zhang, N. Dong, Y. Huang, H. Zhou, M. Xie, E.W.C. Chan, et al.. Evolution of tigecycline- and colistin-resistant CRKP (carbapenem-resistant Klebsiella pneumoniae) in vivo and its persistence in the GI tract. Emerg Microbes Infect, 7 ( 2018), p. 127
[23]
D. Saeloh, V. Tipmanee, K.K. Jim, M.P. Dekker, W. Bitter, S.P. Voravuthikunchai, et al.. The novel antibiotic rhodomyrtone traps membrane proteins in vesicles with increased fluidity. PLoS Pathog, 14 (2) ( 2018), Article e1006876
[24]
A. Sabnis, K.L. Hagart, A. Klöckner, M. Becce, L.E. Evans, R.C.D. Furniss, et al.. Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane. eLife, 10 ( 2021), p. e65836
[25]
F.P. Altman. Tetrazolium salts and formazans. Prog Histochem Cytochem, 9 (3) ( 1976), pp. 1-51
[26]
E. Ansó, S.E. Weinberg, L.P. Diebold, B.J. Thompson, S. Malinge, P.T. Schumacker, et al.. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol, 19 (6) ( 2017), pp. 614-625
[27]
S. Meylan, C.B.M. Porter, J.H. Yang, P. Belenky, A. Gutierrez, M.A. Lobritz, et al.. Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control. Cell Chem Biol, 24 (2) ( 2017), pp. 195-206
[28]
G. Orazi, K.L. Ruoff, G.A. O’Toole. Pseudomonas aeruginosa increases the sensitivity of biofilm-grown Staphylococcus aureus to membrane-targeting antiseptics and antibiotics. MBio, 10 (4) ( 2019), pp. e01501-e1519
[29]
T. Parasassi, E. Gratton. Membrane lipid domains and dynamics as detected by Laurdan fluorescence. J Fluoresc, 5 (1) ( 1995), pp. 59-69
[30]
G. Fang, W. Li, X. Shen, J.M. Perez-Aguilar, Y. Chong, X. Gao, et al.. Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria. Nat Commun, 9 ( 2018), p. 129
[31]
S.A. Baron, J.M. Rolain. Efflux pump inhibitor CCCP to rescue colistin susceptibility in mcr-1 plasmid-mediated colistin-resistant strains and Gram-negative bacteria. J Antimicrob Chemother, 73 (7) ( 2018), pp. 1862-1871
[32]
Y.H. Cheng, T.L. Lin, Y.T. Lin, J.T. Wang. A putative RND-type efflux pump, H239_3064, contributes to colistin resistance through CrrB in Klebsiella pneumoniae. J Antimicrob Chemother, 73 (6) ( 2018), pp. 1509-1516
[33]
E. Cabezón, J. Ripoll-Rozada, A. Peña, F. de la Cruz, I. Arechaga. Towards an integrated model of bacterial conjugation. FEMS Microbiol Rev, 39 (1) ( 2015), pp. 81-95
[34]
H. Huang, J. Liao, X. Zheng, Y. Chen, H. Ren. Low-level free nitrous acid efficiently inhibits the conjugative transfer of antibiotic resistance by altering intracellular ions and disabling transfer apparatus. Water Res, 158 ( 2019), pp. 383-391
[35]
Y. Wang, J. Lu, L. Mao, J. Li, Z. Yuan, P.L. Bond, et al.. Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera. ISME J, 13 (2) ( 2019), pp. 509-522
[36]
J.W. Beaber, B. Hochhut, M.K. Waldor. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature, 427 (6969) ( 2004), pp. 72-74
[37]
K. Pěnčíková, P. Kollár, V.M. Závalová, E. Táborská, J. Urbanová, J. Hošek. Investigation of sanguinarine and chelerythrine effects on LPS-induced inflammatory gene expression in THP-1 cell line. Phytomedicine, 19 (10) ( 2012), pp. 890-895
[38]
S.J. Chmura, M.E. Dolan, A. Cha, H.J. Mauceri, D.W. Kufe, R.R. Weichselbaum. In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. Clin Cancer Res, 6 (2) ( 2000), pp. 737-742
[39]
U. Platzbecker, J.L. Ward, H.J. Deeg. Chelerythrin activates caspase-8, downregulates FLIP long and short, and overcomes resistance to tumour necrosis factor-related apoptosis-inducing ligand in KG1a cells. Br J Haematol, 122 (3) ( 2003), pp. 489-497
[40]
M. Valipour, A. Zarghi, M.A. Ebrahimzadeh, H. Irannejad.Therapeutic potential of chelerythrine as a multi-purpose adjuvant for the treatment of COVID-19. Cell Cycle, 20 (22) ( 2021), pp. 2321-2336
[41]
X. Huang, M. Yang, J. Lei. Research of celandine in the treatment of cough and asthma. Jilin J Chin Med, 37 (7) ( 2017), pp. 725-776
[42]
B. Li, J.Q. Zhang, X.G. Han, Z.L. Wang, Y.Y. Xu, J.F. Miao. Macleaya cordata helps improve the growth-promoting effect of chlortetracycline on broiler chickens. J Zhejiang Univ Sci B, 19 (10) ( 2018), pp. 776-784
[43]
C.Y. Huang, Y.J. Huang, Z.Y. Zhang, Y.S. Liu, Z.Y. Liu.Metabolism and tissue distribution of chelerythrine and effects of Macleaya cordata extracts on liver NAD(P)H quinone oxidoreductase. Front Vet Sci, 8 ( 2021), p. 659771
[44]
W. Wang, L.C. Dolan, S. von Alvensleben, M. Morlacchini, G. Fusconi. Safety of standardized Macleaya cordata extract in an eighty-four-day dietary study in dairy cows. J Anim Physiol Anim Nutr, 102 (1) ( 2018), pp. e61-e68
[45]
QYResearch.2023-2029 Global and China Macleaya cordata extract industry research and 14th Five Year Plan analysis report. Report. Beijing: QYResearch; 2022.
[46]
L. Gao, H.J. Schmitz, K.H. Merz, D. Schrenk. Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes. Toxicol Lett, 311 ( 2019), pp. 91-97
[47]
J. Wang, Y. Song, N. Zhang, N. Li, C. Liu, B. Wang. Using liposomes to alleviate the toxicity of chelerythrine, a natural pkc inhibitor, in treating non-small cell lung cancer. Front Oncol, 11 ( 2021), Article 658543
[48]
N. Hu, M. Chen, Y. Liu, Q. Shi, B. Yang, H. Zhang, et al.. Pharmacokinetics of sanguinarine, chelerythrine, and their metabolites in broiler chickens following oral and intravenous administration. J Vet Pharmacol Ther, 42 (2) ( 2019), pp. 197-206
[49]
M. Song, Y. Liu, X. Huang, S. Ding, Y. Wang, J. Shen, et al.. A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram-negative pathogens. Nat Microbiol, 5 (8) ( 2020), pp. 1040-1050
[50]
M.R. Yeaman, N.Y. Yount. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev, 55 (1) ( 2003), pp. 27-55
[51]
A. Müller, M. Wenzel, H. Strahl, F. Grein, T.N.V. Saaki, B. Kohl, et al.. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc Natl Acad Sci USA, 113 (45) ( 2016), pp. E7077-E7086
[52]
W. Kim, G. Zou, T.P.A. Hari, I.K. Wilt, W. Zhu, N. Galle, et al.. A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci USA, 116 (33) ( 2019), pp. 16529-16534
[53]
J.L. Dombach, J.L.J. Quintana, C.S. Detweiler. Staphylococcal bacterial persister cells, biofilms, and intracellular infection are disrupted by JD1, a membrane-damaging small molecule. MBio, 12 (5) ( 2021), pp. e01801-e01821
[54]
N.C.S. Mykytczuk, J.T. Trevors, L.G. Leduc, G.D. Ferroni. Fluorescence polarization in studies of bacterial cytoplasmic membrane fluidity under environmental stress. Prog Biophys Mol Biol, 95 (1-3) ( 2007), pp. 60-82
[55]
M. Löffler, J.D. Simen, G. Jäger, K. Schäferhoff, A. Freund, R. Takors. Engineering E. coli for large-scale production—strategies considering ATP expenses and transcriptional responses. Metab Eng, 38 ( 2016), pp. 73-85
[56]
T. Yu, Y.J. Zhou, M. Huang, Q. Liu, R. Pereira, F. David, et al.. Reprogramming yeast metabolism from alcoholic fermentation to lipogenesis. Cell, 174 (6) ( 2018), pp. 1549-1558.e14
[57]
Y. Guo, X. Lv, Y. Wang, Y. Zhou, N. Lu, X. Deng, et al.. Honokiol restores polymyxin susceptibility to MCR-1-positive pathogens both in vitro and in vivo. Appl Environ Microbiol, 86 (5) ( 2020), p. e02346-19
[58]
Y. Wang, J. Lu, S. Zhang, J. Li, L. Mao, Z. Yuan, et al.. Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation. ISME J, 15 (9) ( 2021), pp. 2493-2508
[59]
Getino M, Sanabria-Ríos DJ, Fernández-López R, Campos-Gómez J, Sánchez-López JM, Fernández A, et al. Synthetic fatty acids prevent plasmid-mediated horizontal gene transfer. MBio 2015;6( 5):e01032-e15.
[60]
W.D. Qian, J. Huang, J.N. Zhang, X.C. Li, Y. Kong, T. Wang, et al.. Antimicrobial and antibiofilm activities and mechanism of action of chelerythrine against carbapenem-resistant Serratia marcescens in vitro. Microb Drug Resist, 27 (8) ( 2021), pp. 1105-1116
[61]
N. Kajarabille, G.O. Latunde-Dada.Programmed cell-death by ferroptosis: antioxidants as mitigators. Int J Mol Sci, 20 (19) ( 2019), p. 4968
PDF(2234 KB)

Accesses

Citation

Detail
段落导航
相关文章

/

〈 〉