MOLECULES
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2025
·Vol. 30
·期 10
·2122
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IF 4.6
Zhinan Wang,Xiaowei Li,Liang Zhao,Saiwa Liu,Jingjing Du,Xi Jia,Lirui Ge,Jian Xu,Kexin Cui,Yu Ga,Jinxiu Wang,Xi Xia
The emergence ofmcr-1-mediated colistin resistance has become a critical global health concern, highlighting the urgent need for innovative approaches to restore colistin’s therapeutic potential. In this study, we evaluated the antibacterial activity of four matrine-type alkaloids—namely, matrine, oxymatrine, sophocarpine, and sophoramine—againstmcr-1-positiveEscherichia coli. While these alkaloids showed limited efficacy when used alone, the combination of matrine with colistin exhibited remarkable synergistic effects, as demonstrated by checkerboard assays and time-kill curve analyses. The matrine–colistin combination caused minimal erythrocyte damage while effectively attenuating resistance development in vitro. This synergy was further corroborated in a murine infection model, where the combination significantly reduced bacterial loads in target tissues. Mechanistic studies revealed that the matrine–colistin combination enhances antimicrobial activity by disrupting bacterial membrane integrity, increasing intracellular colistin accumulation, and triggering reactive oxygen species-mediated oxidative damage. Collectively, these findings highlight the potential of matrine as a promising adjuvant to overcome colistin resistance, providing a novel therapeutic approach to address the challenge of infections cause by multidrug-resistant Gram-negative bacteria.
研究领域:
微生物学
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药理学
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感染病学
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PubMed
高影响因子
Communications Biology
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2025
·Vol. 8
·期 1
·1-14
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IF 5.1
Xu Tianqi,Fang Dan,Li Fulei,Wang Zhiqiang,Liu Yuan
Antimicrobial resistance poses a severe threat to human health, with colistin serving as a critical medication in clinical trials against multidrug-resistant Gram-negative bacteria. However, the efficacy of colistin is increasingly compromised due to the rise of MCR-positive bacteria worldwide. Here, we reveal a notable metabolic disparity between mcr -positive and -negative bacteria through transcriptome and metabolomics analysis. Specifically, pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, was significantly diminished in mcr -positive bacteria. Conversely, supplementing with PLP could reverse the metabolic profile of drug-resistant bacteria and effectively restore colistin’s bactericidal properties. Mechanistically, PLP was found to augment bacterial proton motive force by inhibiting the Kdp transport system, a bacterial K + transport ATPase, thereby facilitating the binding of the positively charged colistin to the negatively charged bacterial membrane components. Furthermore, PLP supplementation triggers ferroptosis-like death by accumulating ferrous ions and inducing lipid peroxidation. These two modes of action collectively resensitize mcr -harboring Gram-negative bacteria to colistin therapy. Altogether, our study provides a novel metabolic-driven antibiotic sensitization strategy to tackle antibiotic resistance and identifies a potentially safe antibiotic synergist.
研究领域:
微生物学
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药理学
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代谢组学
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DOI
PubMed
高影响因子
eLife
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2025
·
IF 0
Yajun Zhai,Peiyi Liu,Xueqin Hu,Changjian Fan,Xiaodie Cui,Qibiao He,Dandan He,Xiaoyuan Ma,Gongzheng Hu
Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections.
研究领域:
微生物学
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药理学
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传染病学
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耐药性
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DOI
PubMed
BIOMEDICINE & PHARMACOTHERAPY
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2022
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IF 7.419
Kaifang Yi,Shuobo Liu,Peiyi Liu,Xingwei Luo,Jinfeng Zhao,Fengbin Yan,Yushan Pan,Jianhua Liu,Yajun Zhai,Gongzheng Hu
It has been recognized that colistin resistance is a growing problem that seriously impairs the clinical efficacy of colistin against bacterial infections. One strategy that has been proven to have therapeutic effect is to overcome the widespread emergence of antibiotic-resistant pathogens by combining existing antibiotics with promising non-antibiotic agents. In this work, antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the individual drugs and the potential synergistic activity of the combination. The molecular mechanisms of tetrandrine in combination with colistin were analyzed using fluorometric assay and Real-time PCR. To predict possible interactions between tetrandrine and MCR-1, molecular docking assay was taken. Finally, we evaluated the in vivo efficacy of tetrandrine in combination with colistin against MCR-positive Salmonella . Overall, the combination of tetrandrine and colistin showed significant synergistic activity. In-depth mechanistic analysis showed that the combination of tetrandrine with colistin enhances the membrane-damaging ability of colistin, undermines the functions of proton motive force (PMF) and efflux pumps in MCR-positive bacteria. The results of molecular docking and RT-PCR analyses showed that tetrandrine not only affects the expression of mcr -1 but is also an effective MCR-1 inhibitor. Compared with colistin monotherapy, the combination of tetrandrine with colistin significantly reduced the bacterial load in vivo. Our findings demonstrated that tetrandrine serves as a potential colistin adjuvant against MCR-positive Salmonella .
研究领域:
微生物学
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药理学
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传染病学
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分子生物学
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DOI
PubMed
高影响因子
Animals
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2025
·Vol. 15
·期 23
·3491
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IF 2.7
Yongjie Zhang,Liyang Guo,Shun Wang,Jie Zhang,Xinlei Ren,Rui Li,Jichang Li,Chunli Chen
Simple SummaryPolymyxin E is widely considered the last resort for treating multidrug-resistant Gram-negative bacteria. However, due to the emergence of the plasmid-mediated MCR-1 resistance gene, an increasing number of strains have developed resistance to polymyxin E. Additionally, the prevalence ofEscherichia coliin chickens has imposed a heavy burden on the global food and poultry farming industries. This study aimed to investigate the in vitro and in vivo synergistic effects and mechanisms of quercetin (QUE) combined with polymyxin E against MCR-1-positiveE. coliJD37 from chickens. The in vitro and in vivo synergistic effects of QUE and polymyxin E were confirmed through in vitro drug sensitivity tests, growth curves, time-kill curves, agar diffusion tests, and in vivo chick infection experiments. The results showed that QUE restored the sensitivity of polymyxin E toE. coliJD37 and restored the sensitivity of polymyxin E toE. coliJD37 mainly by increasing the permeability of the cell membrane, elevating the fluidity of the cell membrane, increasing the membrane potential, and reducing the expression of the AcrAB-TolC efflux pump and Lipopolysaccharide (LPS) regulatory-related genes. Molecular docking results revealed the key binding sites of QUE to MCR-1.In animal husbandry and livestock farming, with the spread of the plasmid-mediated MCR-1 gene, polymyxin E, as the last line of defense against drug-resistant Gram-negative bacteria, is facing severe challenges. This study investigated the in vitro and in vivo synergistic effects and mechanisms of QUE combined with polymyxin E against MCR-1-positive chickenE. coliJD37. In vitro experiments showed that QUE could restore the sensitivity ofE. coliJD37 to polymyxin E (FIC = 0.34375) and enhance the bactericidal effect of polymyxin E by increasing cell membrane permeability, fluidity, and membrane potential, downregulating the expression of the AcrAB-TolC efflux pump and LPS-related genes. Molecular docking further identified the key residues for QUE binding to the MCR-1 protein. The in vivo chick infection model confirmed that combination therapy increased survival rates, reduced bacterial load in tissues, alleviated pathological damage, and decreased levels of intestinal inflammatory factors. Our results demonstrate the synergistic bactericidal effect of the QUE-polymyxin E combination against MCR-1-positiveE. coliand elucidate its underlying mechanism.
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PubMed
高影响因子
Journal of Global Antimicrobial Resistance
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2022
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IF 4.349
Wenting Zhang,Tengfei Zhang,Chen Wang,Guixing Liang,Qin Lu,Guoyuan Wen,Yunqing Guo,Yiluo Cheng,Zui Wang,Huabin Shao,Qingping Luo
ABSTRACT Objectives This study investigated the prevalence and characteristics of mcr-1- harbouring Escherichia coli isolated from chickens in central China from 2014 to 2019. Methods A total of 1132 E. coli isolated from 1647 chicken swabs were analysed for colistin susceptibility by broth microdilution method and prevalence of mcr-1 gene by PCR. The colistin-resistant E. coli isolates were typed by multi-locus sequence typing (MLST) and tested with 12 antimicrobial agents. The transconjugation assay was conducted for the mcr-1 -positive isolates using the transconjugant E. coli C600. Results Of the 1132 E. coli isolated from chickens, 131 isolates (11.6%) exhibited colistin resistance, and 51 isolates (4.5%) were mcr-1 positive. The mcr-1 -positive rate was quite low in 2014 (2.3%) and 2015 (1.7%), increased to peak in 2016 (12.6%) and 2017 (11.4%), and then decreased significantly in 2018 (1.7%) and 2019 (0.9%). The 131 colistin resistant isolates were assigned to 66 unique sequence types (STs), 27 of which contained mcr-1 -positive isolates. Compared with mcr-1 -negative E. coli, mcr-1 -positive E. coli showed higher resistance rates to nalidixic acid, ciprofloxacin, ceftriaxone, cefotaxime, and tetracycline. Furthermore, 30 of the 51 mcr-1 positive isolates transduced their mcr-1 gene into E. coli C600, and 13 of the 30 transconjugants carried more than one replicon types. Conclusion The mcr-1 positive rate varied enormously during 2014–2019 in central China. The ban on colistin likely decreased the dissemination of mcr-1 in E. coli isolates from chickens. Multidrug-resistant trait is observed in mcr-1 positive E. coli isolates and can be transferred into other transconjugants.
研究领域:
微生物学
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兽医学
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公共卫生
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分子生物学
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DOI
PubMed
高影响因子
Revista Brasileira de Farmacognosia-Brazilian Journal of Pharmacognosy
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2024
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IF 1.4
Yao Xinyu,Shu Yang,Xu Lei,Wei Lijuan,Cui Minhe,Li Li,Zhang Peng,Fang Tianqi
Colistin is recognized as the “last line of defense” for the treatment of carbapenemase-producing “super-resistant” bacteria. However, the treatment of clinical bacterial infections has become more challenging due to the widespread prevalence of the novel resistance gene mcr-1 in multidrug-resistant pathogens. Currently, the use of natural compounds as novel adjuvants to colistin treatment is a safe, feasible, and promising approach compared to the high cost and unpredictability of developing novel antimicrobial drugs. Here, we identified a potential MCR-1 inhibitor, ursodeoxycholic acid, that may be used to treat infections caused by MCR-1-positive drug-resistant bacteria. In this study, checkerboard minimum inhibitory concentration assays demonstrated that ursodeoxycholic acid could reduce the MICs of colistin-resistant strains 4–64 times. Furthermore, a time-kill curve analysis, combined with disk diffusion testing and live/dead bacterial staining, demonstrated that ursodeoxycholic acid could effectively enhance the antibacterial activity of colistin, and when the concentration of ursodeoxycholic acid was lower than 512 μg/ml, it did not affect the normal growth of bacteria; thus, ursodeoxycholic acid imparts less selective pressure on bacteria and did not easily induce the emergence of drug resistance. In addition, through potential target prediction, molecular docking, RT-PCR analysis, membrane permeability detection, and scanning electron microscopy analysis, we demonstrated that ursodeoxycholic acid can form a complex with MCR-1, suggesting that UDCA may affect the activity of MCR-1. In addition, ursodeoxycholic acid combined with colistin was able to alter the electronegativity and permeability of the bacterial membrane, thereby disrupting the structural integrity of the bacterial membranes and significantly enhancing membrane damage–associated colistin activity. In summary, our findings indicate that the colistin/ursodeoxycholic acid combination may be a promising alternative approach for treating MCR-1-positive bacterial infections. Graphical Abstract
研究领域:
微生物学
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药理学
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传染病学
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分子生物学
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DOI
高影响因子
Microbial Biotechnology
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2023
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IF 5.7
Xinyue Ye,Jian Wang,Pengfei Xu,Xiaoqian Yang,Qixue Shi,Genyan Liu,Zhaoshi Bai,Changlin Zhou,Lingman Ma
Polymyxin resistance is conferred by MCR-1 (mobile colistin resistance 1)-induced lipopolysaccharide (LPS) modification of G − bacteria. However, the peptide MSI-1 exerts potent antimicrobial activity against mcr-1 -carrying bacteria . To further investigate the potential role of MCR-1 in improving bacterial virulence and facilitating immune evasion, and the immunomodulatory effect of peptide MSI-1, we first explored outer membrane vesicle (OMV) alterations of mcr-1 -carrying bacteria in the presence and absence of sub-MIC MSI-1, and host immune activation during bacterial infection and OMV stimulation. Our results demonstrated that LPS remodelling induced by MCR-1 negatively affected OMV formation and protein cargo by E. coli . In addition, MCR-1 diminished LPS-stimulated pyroptosis but facilitated mitochondrial dysfunction, further aggravating apoptosis in macrophages induced by OMVs of E. coli . Similarly, TLR4-mediated NF-κB activation was markedly alleviated once LPS was modified by MCR-1. However, peptide MSI-1 at the sub-MIC level inhibited the expression of MCR-1, further partly rescuing OMV alteration and attenuation of immune responses in the presence of MCR-1 during both infection and OMV stimulation, which can be exploited for anti-infective therapy.
研究领域:
微生物学
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免疫学
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药理学
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DOI
PubMed
高影响因子
Research
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2023
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IF 11
Tianqi Xu,Dan Fang,Fulei Li,Zhiqiang Wang,Yuan Liu
The emergence of antibiotic tolerance, characterized by the prolonged survival of bacteria following antibiotic exposure, in natural bacterial populations, especially in pathogens carrying antibiotic resistance genes, has been an increasing threat to public health. However, the major causes contributing to the formation of antibiotic tolerance and underlying molecular mechanisms are yet poorly understood. Herein, we show that potassium sorbate (PS), a widely used food additive, triggers a high level of fluoroquinolone tolerance in bacteria carrying mobile colistin resistance gene mcr. Mechanistic studies demonstrate that PS treatment results in the accumulation of intracellular fumarate, which activates bacterial two-component system and decreases the expression level of outer membrane protein OmpF, thereby reducing the uptake of ciprofloxacin. In addition, the supplementation of PS inhibits aerobic respiration, reduces reactive oxygen species production and alleviates DNA damage caused by bactericidal antibiotics. Furthermore, we demonstrate that succinate, an intermediate product of the tricarboxylic acid cycle, overcomes PS-mediated ciprofloxacin tolerance. In multiple animal models, ciprofloxacin treatment displays failure outcomes in PS preadministrated animals, including comparable survival and bacterial loads with the vehicle group. Taken together, our works offer novel mechanistic insights into the development of antibiotic tolerance and uncover potential risks associated with PS use.
研究领域:
微生物学
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药理学
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公共卫生
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分子生物学
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DOI
高影响因子
Arabian Journal of Chemistry
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2024
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IF 5.3
Ping Cheng,Botao Wang,Shuying Liang,Yuqi Yang,Shixin Gui,Kai Zhang,Yingying Sun,Shaoqi Qu,Lin Li
Colistin used to be regarded as the last-resort treatment for the infection caused by multidrug-resistant gram-negative bacteria. However, the emergence and widespread of mcr-1 seriously reduce the clinical effectiveness of colistin, constituting a serious threat to global public health. Due to the difficulties in the development of new antibiotics, restoring antibiotic susceptibility with adjuvants is undoubtedly a rational option. As naturally occurring compounds, resveratrol and capsaicin could be extracted from many natural plants, due to various antimicrobial properties, they have received significant attention. Herein, the synergistic activity of colistin combined with resveratrol and capsaicin against mcr-1 -positive Escherichia coli were investigated by checkerboard method and time-killing assays. The in-depth molecular mechanisms were elucidated by scanning electron microscopy, fluorescent probe experiments, transcriptome and metabolome analysis. Molecular docking assay was taken to analyse potential interactions between resveratrol/capsaicin and MCR-1. Finally, the in vivo efficacy of combined therapy against mcr-1- positive Escherichia coli was assessed. Our results demonstrated that colistin combined with resveratrol and capsaicin acted synergistic activity against mcr-1- positive Escherichia coli both in vivo and in vitro . Further mechanistic studies showed that the combined therapy could exacerbate cell membrane damage, increase membrane permeability, disrupt the homeostasis of PMF, inhibit ATP synthesis, and efflux pump activity. In addition, the combined therapy could inhibit central carbon metabolism, and reduce tricarboxylic acid cycle and oxidative phosphorylation. Moreover, molecular docking assay revealed resveratrol/capsaicin could bind to MCR-1 stably. Our study indicated that colistin in combination with resveratrol and capsaicin as a novel therapy could provide a trustworthy foundation to establish the treatment plan for mcr-1- positive Escherichia coli.
研究领域:
微生物学
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药理学
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分子生物学
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传染病学
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DOI
高影响因子
Theranostics
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2020
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IF 8.579
Yuan Liu,Yuqian Jia,Kangni Yang,Ziwen Tong,Jingru Shi,Ruichao Li,Xia Xiao,Wenkai Ren,Rüdiger Hardeland,Russel J. Reiter,Zhiqiang Wang
Background: Emergence, prevalence and widely spread of plasmid-mediated colistin resistance in Enterobacteriaceae strongly impairs the clinical efficacy of colistin against life-threatening bacterial infections. Combinations of antibiotics and FDA-approved non-antibiotic agents represent a promising means to address the widespread emergence of antibiotic-resistant pathogens. Methods: Herein, we investigated the synergistic activity between melatonin and antibiotics against MCR (mobilized colistin resistance)-positive Gram-negative pathogens through checkerboard assay and time-killing curve. Molecular mechanisms underlying its mode of action were elucidated. Finally, we assessed the in vivo efficacy of melatonin in combination with colistin against drug-resistant Gram-negative bacteria. Results: Melatonin, which has been approved for treating sleep disturbances and circadian disorders, substantially potentiates the activity of three antibiotics, particularly colistin, against MCR-expressing pathogens without enhancing its toxicity. This is evidence that the combination of colistin with melatonin enhances bacterial outer membrane permeability, promotes oxidative damage and inhibits the effect of efflux pumps. In three animal models infected by mcr-1 -carrying E. coli , melatonin dramatically rescues colistin efficacy. Conclusion: Our findings revealed that melatonin serves as a promising colistin adjuvant against MCR-positive Gram-negative pathogens.
研究领域:
微生物学
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药理学
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传染病学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Yanhu Huang,Zhiqiang Wang,Ziyi Liu,Quanmin Huan,Yuan Liu,Ruichao Li,Mianzhi Wang,Xia Xiao
Background The emergence and wide spread of plasmid-mediated colistin resistance gene ( mcr-1 ) and its mutants have immensely limited the efficacy of colistin in treating multidrug-resistant (MDR) Gram-negative bacterial infections. The development of synergistic combinations of antibiotics with a natural product that coped with the resistance of MDR bacteria was an economic strategy to restore antibiotics activity. Herein, we investigated gigantol, a bibenzyl phytocompound, for restoring in vitro and in vivo , the sensitivity of mcr -positive bacteria to colistin. Methods The synergistic activity of gigantol and colistin against multidrug-resistant Enterobacterales was studied via checkerboard assay and time-killing curve. Subsequently, the transcription and protein expression levels of mcr -1 gene were determined by RT-PCR and Western blots. The interaction of gigantol and MCR-1 was simulated via molecular docking and verified via site-directed mutagenesis of MCR-1. Hemolytic activity and cytotoxicity assay were used to evaluate the safety of gigantol. Finally, the in vivo synergistic effect was evaluated via two animal infection models. Results Gigantol restored the activity of colistin against mcr -positive bacteria E.coli B2 (MIC from 4 μg/ml to 0.25 μg/ml), Salmonella 15E343 (MIC from 8 μg/ml to 1 μg/ml), K. pneumoniae 19-2-1 (MIC from 32 μg/ml to 2 μg/ml) carrying mcr -1, mcr -3, mcr -8, respectively. Mechanistic studies revealed that gigantol down-regulated the expression of genes involved in LPS-modification, reduced the MCR-1 products and inhibited the activity of MCR-1 by binding to amino acid residues Tyr287 and Pro481 in its D-glucose-binding pocket. Safety evaluation showed that the addition of gigantol relieves the hemolysis caused by colistin. Compared with monotherapy, the combination of gigantol and colistin significantly improved the survival rate of Gallgallella mellonella larvae and mice infected by E.coli B2. Moreover, there was a considerable decrease in the bacterial load present in the viscera of mice. Conclusion Our results confirmed that gigantol was a potential colistin adjuvant, and could be used to tackle multi-drug resistant Gram-negative pathogen infections combined with colistin.
研究领域:
微生物学
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药理学
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传染病学
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分子生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）