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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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
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
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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产品关联
DOI
PubMed
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
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
CURRENT MICROBIOLOGY
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2026
·Vol. 83
·期 8
·424
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IF 2.8
Xu Jialin,Yan Bohu,Fu Qifu,Li Haoyu,Jiang Zonghan,Zhou Rushun,Chen Xiaojun,Sun Zhiliang,Wang Yanan,Li Jiyun
In response to the critical challenge of colistin resistance in animal production, we examined the occurrence and genetic features of mcr-1 -positive E. coli isolates collected from livestock in Hunan province, China, between 2016 and 2021. A total of 1,358 animal samples from chickens and pigs were collected and screened. Monitoring data indicates that nineteen mcr-1 -positive E. coli isolates (1.40%) were identified, and all were resistant to colistin and tetracycline. The prevalence rate of mcr-1 positive E. coli has significantly declined since 2017 and has remained consistently low. Most isolates (89.47%) exhibited multidrug resistance and carried multiple antibiotic resistance genes, including tet (A) , sul3, bla TEM-1B, while a subset of strains (21.05%) harbored quinolone resistance-associated point mutations in gyrA , parC , and parE . Multi-locus sequence typing identified 14 sequence types, with ST48 being the most frequent (21.05%), and five clonal complexes, with CC10 as the predominant lineage (52.63%). Plasmid analysis revealed that 68.42% of the isolates carried plasmids, predominantly IncX4 (36.84%), and 57.89% of isolates harbored conjugative plasmids with complete relaxase and MPF system components. The mcr-1 gene was found within three main genetic arrangements: (i) mcr-1-pap2, (ii)IS Apl1-mcr-1-pap2, and (iii) IS Apl1-mcr-1-pap2- IS Apl1 . These findings highlight the potential for dissemination of mcr-1 in animal-derived E. coli and underscore the importance of monitoring and controlling antimicrobial resistance in livestock.
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Chunxia Hu,Jinyong Zhang,Ruiqin Cui,Shiyi Liu,Ying Huang,Huan Zeng,Shumin Cheng,Guibao Zhou,Jingli Li,Longqin Sun,Yan Zhao,Xiao Wang,Jianhua Liu,Quanming Zou,Wei Huang
Given the important role of polymyxin B (PB) in the treatment of drug-resistant Gram-negative bacterial infections, the emergence of PB resistance poses a serious threat to public health. Adjuvant development is a supplementary strategy that can compensate for the lack of novel antibiotics by protecting PB. In this study, we found a small molecule named Lyb24 that showed weak antibacterial activity (minimum inhibitory concentration ≥ 10 μg/ml) but potentiated and revitalized the efficacy of PB against Gram-negative pathogens, including mcr-1 - and mgrB -deletion-mediated PB-resistant strains. Our results showed that Lyb24 inhibits the translational levels of genes associated with the modification of lipid A. In addition, Lyb24 increases the permeability, disrupts the integrity and induces the depolarization of the membrane. We further found that both Lyb24 and PB could directly bind to AzoR and inhibit its activity. Structural analysis showed that Lyb24 binds to the isoalloxazine ring of flavin mononucleotide (FMN) through pi-pi stacking and loop η4 of AzoR. A pneumonia model was used to confirm that the activity against clinical PB-resistant Klebsiella pneumoniae was enhanced due to Lyb24 on PB. In conclusion, we provide a potential therapeutic regimen by combining Lyb24 and PB to treat Gram-negative-resistant bacterial infections. Our findings not only explain the synergistic effect of Lyb24, but also expand our knowledge on the mechanism of action of PB.
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
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Linlin Ding,Rui He,Yongjia Hu,Jian Liu,Paizati Hamidi,Yerzati Nurman,Lei Xu,Jianfeng Wang,Xuming Deng,Aslebek Zekriya,Ying Chen,Qingjie Li
The global spread of multidrug-resistant (MDR) bacteria is devastating health systems and economies worldwide, and this critical trend has revitalized antibiotic adjuvant research. The extensive dissemination of plasmid- or chromosome-mediated resistance genes emphasizes the importance of reshaping colistin sensitivity. Here, we report the discovery that Melissa officinalis essential oil isolated from Traditional Chinese medicine, effectively potentiates the bactericidal activities of colistin against mobile colistin resistance (MCR-1) positive Escherichia coli ( E. coli ). Mechanistic analysis demonstrated that Melissa officinalis essential oil interacts with the MCR-1 protein to disrupt LPS modification, while concurrently inducing microbial iron homeostasis disruption and oxidative damage. To enhance its essential oil-mediated therapeutic potential in clinical management, Melissa officinalis essential oil-loaded nanostructured lipid carrier (MOEO-NLC) was designed with improved biocompatibility and solubility. Encouragingly, the combination of MOEO-NLC and colistin reduced bacterial burden reduction and inflammatory response suppression in a peritonitis-sepsis model. Collectively, this study advances antibacterial tactics and underscores the transformative potential of MOEO-NLC in paving the way for enduring countermeasures against antibiotic-resistant threats.
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DOI
高影响因子
eLife
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2025
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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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产品关联
DOI
PubMed
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
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2023
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IF 5.2
Sheng Qiushuang,Wang Nan,Zhou Yonglin,Deng Xuming,Hou Xiaoning,Wang Jianfeng,Qiu Jiazhang,Deng Yanhong
BackgroundAdjuvant addition of approved drugs or foodborne additives to colistin might be a cost-effective strategy to overcome the challenge of plasmid-mediated mobile colistin resistance gene emergence, which poses a threat in the clinic and in livestock caused by infections with Gram-negative bacteria, especially carbapenem-resistant Enterobacteriaceae.MethodsChequerboard assay was applied to screen the colistin adjuvants from natural compounds. The killing–time curve, combined disc test and membrane permeation assay were conducted to identify the synergy efficacy of thymol and colistin in vitro. Thin-layer chromatography (TLC), LC-MS and fluorescence spectra were used to indicate the interaction of thymol and MCR-1. The potential binding sites were then investigated by molecular simulation dynamics. Finally, a thymol nanoemulsion was prepared with high-pressure homogenization as the clinical dosage form.ResultsThymol presented an excellent synergistic effect in vitro with colistin against Salmonella enterica serovar Typhimurium and Escherichia coli bacteria. Thymol addition, forming a complex with MCR-1, might interfere with the efficacy of MCR-1. Moreover, thymol strengthened colistin activity associated with potentiating membrane damage, destroying the biofilm and enhancing reactive oxygen species-mediated oxidative damage. Thymol nanoemulsion combined with colistin remarkably prevented the intestinal damage caused by S. Typhimurium infection, resulting in a survival rate higher than 60%.ConclusionsThis study achieved a promising thymol oral formulation as colistin adjuvant to combat S. Typhimurium infection, which could be used to extend the lifespan of colistin in clinical veterinary medicine.
研究领域:
微生物学
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药学
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传染病学
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兽医学
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DOI
PubMed
高影响因子
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
✓ 已验证
DOI
PubMed
高影响因子
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