Journal of Advanced Research
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2021
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IF 10.479
Xueyang Jin,Ming Zhang,Jinghui Lu,Ximeng Duan,Jinyao Chen,Yue Liu,Wenqiang Chang,Hongxiang Lou
Introduction The increasing morbidity of fungal infections and the prevalence of drug resistance highlighted the discovery of novel antifungal agents and investigation of their modes of action. Iron chelators have been used to treat superficial fungal infections or potentiate the efficacy of certain antifungal drugs. Hinokitiol exhibits potent antifungal activity and iron-chelating ability. However, their relationships have not been established. Objectives This study aims to explore the selectivity of hinokitiol against fungal cells and mammalian cells and determine the role of iron-chelating for the antifungal activity of hinokitiol. Methods Iron probe FeRhonox-1 was used to determine intracellular Fe 2+ content. 5-Cyano-2,3-ditolyl tetrazolium chloride probe and Cell Counting Kit-8 were used to detect the mitochondrial respiratory activities. Quantitative real-time PCR and rescue experiments were performed to determine the effect of iron on the antifungal activity of hinokitiol. The effects of hinokitiol on fungal mitochondria were further evaluated using reactive oxygen species probes and several commercial Assay Kits. The ability of hinokitiol to induce resistance in Candida species was carried out using a serial passage method. The in vivo therapeutic effect of hinokitiol was evaluated using Galleria mellonella as an infectious model. Results Hinokitiol was effective against a panel of Candida strains with multiple azole-resistant mechanisms and persistently inhibited Candida albicans growth. Mechanism investigations revealed that hinokitiol chelated fungal intracellular iron and inhibited the respiration of fungal cells but had minor effects on mammalian cells. Hinokitiol further inhibited the activities of mitochondrial respiratory chain complexes I and II and reduced mitochondrial membrane potential, thereby decreasing intracellular ATP synthesis and increasing detrimental intracellular reductive stress. Moreover, hinokitiol exhibited low potential for inducing resistance in several Candida species and greatly improved the survival of Candida -infected Galleria mellonella . Conclusions These findings suggested the potential application of hinokitiol as an iron chelator to treat fungal infections.
研究领域:
微生物学
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药理学
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真菌学
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医学真菌学
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DOI
PubMed
高影响因子
Journal of Global Antimicrobial Resistance
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2023
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IF 4.6
Jingchun Kong,Yue Wang,Yijia Han,Huijing Zhou,Zhenyun Huang,Xiaodong Zhang,Cui Zhou,Tieli Zhou,Jianming Cao
Objectives The emergence of carbapenem-resistant Escherichia coli (CREC) is a global concern as its prevalence restricts treatment options and poses a considerable threat to public health. In this study, in vitro and in vivo activity of the antimicrobial peptide Octominin against CREC were evaluated, and investigated its possible mechanism of action was investigated. Furthermore, its safety and factors influencing its antibacterial effect were assessed. Additionally, the anti-inflammatory effects of Octominin were examined. Methods The antimicrobial activity of Octominin against 11 strains of CREC was determined using the broth microdilution method, growth curve, and time-kill assay. Its possible mechanism of action was unraveled using the propidium iodide and N-phenyl-1-naphthylamine fluorochrome and lipopolysaccharide-binding assays. To understand the safety and stability of Octominin, its cytotoxicity, hemolysis, and antibacterial activity under various conditions, such as temperature and ions, were estimated. Additionally, a Galleria mellonella infection model was utilized to evaluate the efficacy of Octominin in vivo , and qRT-PCR was performed to assess its impact on the expression of proinflammatory cytokines. Results Octominin displayed a significant antibacterial effect, with MICs of 4 to 8 μg/mL and MBCs of 8 to 16 μg/mL. Octominin exerted its antibacterial effect by disrupting bacterial membranes. Cytotoxicity and hemolysis tests demonstrated the potential application of Octominin in vivo . The G. mellonella infection model asserted the in vivo efficacy of Octominin. Furthermore, Octominin inhibited the expression of proinflammatory cytokines. Although the temperature had little effect on its the activity, serum and ions reduced activity. Conclusions Octominin is a promising alternative agent with remarkable antibacterial and anti-inflammatory effects for treating infections caused by CREC .
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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免疫学
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DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
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2025
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IF 3.5
Daxing Cao,Guihua Liu,Ying Wang,Xiaoxue Xia
Antibiotic resistance has become a significant global public health challenge, particularly in general surgery, where infections caused by resistant bacteria complicate treatment. This study aims to evaluate the potential of the FDA-disapproved antihistamine astemizole as an antibacterial agent, with a focus on its efficacy against methicillin-resistant S . aureus (MRSA). Astemizole demonstrated significant activity against Gram-positive bacteria, especially MRSA, with MIC and MBC values ranging from 4 to 16 μg/mL and 4–32 μg/mL, respectively. However, astemizole showed minimal activity against Gram-negative bacteria. Further investigations revealed that astemizole killed bacteria by disrupting the bacterial membrane, altering membrane potential, inhibiting ATP production, and inducing reactive oxygen species accumulation. Additionally, The resistance mutation frequency of astemizole was low, with only a minor increase in resistance observed in MRSA after 30 days of selective pressure, significantly less than that of ampicillin. Cytotoxicity and hemolysis assays indicated that astemizole was relatively safe at concentrations effective for bacterial inhibition. The Galleria mellonella infection model further confirmed the efficacy of astemizole against MRSA in vivo . Overall, this study provides new insights into the repurposing of astemizole and suggests its potential as a therapeutic agent to address antibiotic resistance.
研究领域:
药理学
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微生物学
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传染病学
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外科学
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DOI
PubMed
高影响因子
MEDICAL MICROBIOLOGY AND IMMUNOLOGY
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2025
·Vol. 214
·期 1
·1-13
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IF 3
Ding Zhi-Wen,Xu Kai-Zhong,Dar Owias Iqbal,Yin Lu-Jun,Wang Ying-Jie,Liao Yun-tong,Wang Peng,Jia Ai-Qun
Burkholderia cenocepacia , an opportunistic pathogen, poses a significant threat to human health, necessitating the discovery of effective quorum sensing inhibitors (QSIs). In this study, the quorum sensing inhibitory effects of deferiprone (DFP) on the B. cenocepacia 162,638 were validated. Notably, DFP demonstrated an ability to inhibit and disrupt bacterial biofilms, reducing biofilm formation by 44.59% at 1/4 MIC (minimum inhibitory concentration) and 24.32% at 1/8 MIC concentrations. The study also investigated DFP’s impact on motility, virulence, and QS signal levels. LC-MS/MS analysis showed a gradual reduction in the QS molecule C6-HSL as DFP concentrations increased. Additionally, DFP’s non-hemolytic properties and safety profile, as verified in Galleria mellonella infection models, highlighted its biocompatibility. RT-qPCR results further indicated that DFP downregulated QS-related gene expression, particularly those involved in ferric uptake regulation protein (Fur). Molecular docking studies identified Fur as a key target for DFP’s inhibitory action. Collectively, DFP was shown as a potential QSI with practical applications for controlling B. cenocepacia infections.
研究领域:
微生物学
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传染病学
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药理学
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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 PATHOGENESIS
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2022
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IF 3.848
QiMing Tian,SiMin Wei,HongRui Su,ShuMei Zheng,ShuYa Xu,MingJiang Liu,RuoNan Bo,JinGui Li
The continuous emergence of multidrug-resistant (MDR) bacteria has posed an increasingly serious public health threat which urges people to develop some alternatives. Gallic acid (GA) is a natural ingredient in many traditional Chinese medicines , which has many biological activities, such as antibacterial, and antiseptic. Here, clinical isolates of MDR Escherichia coli ( E. coli ) were used to evaluate the antibacterial effect of GA and the underlying mechanism. The results revealed that GA exerted bactericidal activity and inhibited the formation of bacterial biofilm. GA enhanced the activities of ceftiofur sodium or tetracycline against E. coli , and facilitated antibiotic accumulation in bacteria. Further analysis of morphological alterations and efflux pump gene expressions confirmed that GA damaged outer and inner membranes, and suppressed the mRNA expressions of acrA, acrB, tolC, acrD and acrF involved in membrane permeability . In addition, GA showed protective effects against bacterial infection and improved the survival rates of Galleria mellonella and BALB/c mice. These data highlight a better understanding of GA against bacteria and provide an alternative strategy for MDR bacterial infection.
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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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Li Jie,Xiong Wenguang,Zeng Zhenling
The rapid spread of bacteria with plasmid-mediated resistance to antibiotics poses a serious threat to public health. The search for potential compounds that can increase the antibacterial activity of existing antibiotics is a promising strategy for addressing this issue. Methods: Synergistic activity of the FDA-approved agent oxethazine combined with colistin was investigated in vitro using checkerboard assays and time-kill curves. The synergistic mechanisms of their combination of oxethazine and colistin was explored by fluorescent dye, scanning electron microscopy (SEM) and LC-MS/MS. The synergistic efficacy was evaluated in vivo by the Galleria mellonella and mouse sepsis models. Results: In this study, we found that oxethazine could effectively enhance the antibacterial activity of colistin against both mcr-positive andnegative pathogens, and mechanistic assays revealed that oxethazine could improve the ability of colistin to destruct bacterial outer membrane and cytoplasmic membrane permeability. In addition, their combination triggered the accumulation of reactive oxygen species (ROS), causing additional damage to the membrane structure resulting in cell death. Furthermore, oxethazine significantly enhanced the therapeutic efficacy of colistin in two animal models. Conclusion: These results suggested that oxethazine, as a promising antibiotic adjuvant, can effectively enhance colistin activity, providing a potential strategy for treating multidrug-resistant bacteria.
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
CHINESE JOURNAL OF POLYMER SCIENCE
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2022
·Vol. 41
·期 3
·345-355
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IF 3.815
Liu Hui,Liu Xiao,Cao Yuan-Qiao,Liu Ming,Han Miao-Miao,Ji Sheng-Xiang
Antimicrobial peptides (AMPs) have been considered as an alternative to small molecule antibiotics since they are difficult to develop antimicrobial resistance. Hyperbranched polylysine (HPL), an AMP mimics, has gained attention due to its broad-spectrum antibacterial activities, but it also suffers from high toxicity. Here we report a facile strategy to engineer the toxicity of HPL by copolymerizing lysine (K) with a hydrophobic amino acid, e.g. , alanine (A), tryptophan (W) or phenylalanine (F), to afford hyperbranched random copolymers. These copolymers have comparable antibacterial activities to HPL while their cytotoxicities and in vivo toxicities are lowered when the type and content of hydrophobic amino acid and the size of copolymers are optimized. The G. mellonella infection model demonstrates that the copolymers are effective against the S. aureus infection in vivo . The copolymers kill the bacteria through the disruption of cell membranes and the bacteria do not develop resistance to the copolymers.
研究领域:
材料科学
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生物医学工程
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微生物学
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药学
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产品关联
DOI
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Xin-Rong Wang,Hua Zhong,Shan-Shan Ma,Ya-Hui Huang,Wei-Heng Xu,Yan Wang
Background The incidence of invasive fungal diseases (IFDs), represented by Candida albicans infection, is increasing year by year. However, clinically available antifungal drugs are very limited and encounter challenges such as limited efficacy, drug resistance, high toxicity, and exorbitant cost. Therefore, there is an urgent need for new antifungal drugs. Purpose This study aims to find new antifungal compounds from plants, preferably those with good activity and low toxicity, and reveal their antifungal targets. Methods In vitro antifungal activities of compounds were investigated using broth microdilution method, spot assay, hyphal growth assay and biofilm formation assay. Synergistic effects were assessed using broth microdilution checkerboard technique. In vivo antifungal activities were evaluated using Galleria mellonella and murine candidiasis models. Cytotoxicity of compounds was investigated using Cell Counting Kit-8 (CCK-8). Discovery and validation of antifungal targets of compounds were conducted by using monoallelic knockout library of C. albicans , haploinsufficiency profiling (HIP), thermal shift assay (TSA), enzyme inhibitory effect assay, molecular docking, and in vitro and in vivo antifungal studies. Results 814 plant products were screened, among which petroselinic acid (PeAc) was found as an antifungal molecule. As a rare fatty acid isolated from coriander ( Coriandrum sativum ), carrot ( Daucus carota ) and other plants of the Apiaceae family, PeAc had not previously been found to have antifungal effects. In this study, PeAc was revealed to inhibit the growth of various pathogenic fungi, exhibited synergistic effects with fluconazole (FLC), inhibited the formation of C. albicans hyphae and biofilms, and showed antifungal effects in vivo. PeAc was less toxic to mammalian cells. Fructose-1,6-bisphosphate aldolase (Fba1p) was identified as a target of PeAc by using HIP, TSA, enzyme inhibitory effect assay and molecular docking methods. PeAc exerted antifungal effects more effectively on fba1Δ/FBA1 than wild-type (WT) strain both in vitro and in vivo . Conclusions PeAc is an effective and low toxic antifungal compound. The target of PeAc is Fba1p. Fba1p is a promising target for antifungal drug development.
研究领域:
药理学
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微生物学
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真菌学
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植物化学
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药物发现
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产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
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2024
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IF 3.7
Deyi Zhao,Miran Tang,Panjie Hu,Xiaowei Hu,Weijun Chen,Zhexiao Ma,Huanchang Chen,Haifeng Liu,Jianming Cao,Tieli Zhou
Carbapenem-resistant Klebsiella pneumoniae (CRKP) and Escherichia coli (CREC) are frequently detected in clinical settings, restricting the use of carbapenems. Therefore, there is an urgent need for new antimicrobial strategies to address infections caused by CRKP and CREC. This study investigated the antibacterial, anti-biofilm, and anti-inflammatory effects of the cationic antimicrobial peptide Hs02, along with its potential antimicrobial mechanisms against CRKP and CREC. The results revealed that Hs02 had a low minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against CRKP and CREC, effectively eliminating the bacteria within 30 min. Moreover, Hs02 significantly prevents biofilm formation and disrupts the established biofilms. Further mechanistic studies demonstrated that Hs02 specifically targeted and bound to bacterial outer membrane lipopolysaccharides (LPS), disrupted membrane permeability and integrity, which led to intracellular reactive oxygen species (ROS) accumulation. Furthermore, Hs02 neutralized LPS, thereby suppressing the production of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in murine macrophage RAW 264.7 cells. In vitro, hemolysis and cytotoxicity assays confirmed Hs02’s safety at the tested concentrations and proved that Hs02 improved the survival rate of Galleria mellonella larvae. In conclusion, the findings suggest that Hs02’s interaction with LPS and the resulting disruption of membrane integrity may be key factors driving its rapid bactericidal and anti-inflammatory effects.
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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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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