Aug 2026· Microbiology spectrum· 0 citations· 73 references
Medicine
TL;DR
Findings support a working model in which iron limitation-associated physiological stress contributes to the inhibitory effects of taxifolin on C. perfringens growth and colonization-related phenotypes and support its potential use as a plant-derived approach for limiting C. perfringens intestinal colonization.
Abstract
ABSTRACT Flavonoids are plant-derived polyphenols with diverse biological activities; however, the mechanisms by which individual compounds inhibit intestinal pathogens remain unclear. In this study, we found that taxifolin (dihydroquercetin) showed pronounced inhibitory activity against Clostridium perfringens, a major gram-positive enteropathogen, whereas most other bacterial species tested were less affected. Notably, at concentrations below those causing complete growth inhibition, taxifolin significantly impaired mucin adhesion and biofilm formation, indicating suppression of colonization-associated phenotypes rather than bactericidal activity. In an antibiotic-pretreated mouse infection model, oral administration of taxifolin significantly reduced C. perfringens intestinal colonization during the early phase of infection. Mechanistically, proteomic analysis of C. perfringens revealed marked alterations in surface-associated and extracellular proteins, including stress response factors (MreB, LytR, and ClpB), and enzymes linked to iron- and redox-dependent metabolism, consistent with an iron-limiting stress response. Scanning electron microscopy further revealed pronounced cell elongation in taxifolin-treated cells, consistent with impaired cell division under stress conditions. Importantly, Fe2+ supplementation partially restored bacterial growth, normal morphology, mucin adhesion, and biofilm formation, whereas supplementation with other divalent ions failed to restore growth. Similar phenotypes were observed following treatment with the iron-specific chelator 2,2′-bipyridyl. Collectively, our findings support a working model in which iron limitation-associated physiological stress contributes to the inhibitory effects of taxifolin on C. perfringens growth and colonization-related phenotypes. This study provides insights into the interaction between dietary flavonoids and clostridial pathogens, highlighting the potential of taxifolin as a plant-derived compound for limiting C. perfringens intestinal colonization. IMPORTANCE Clostridium perfringens, a clinically important pathogen in both humans and animals, causes various histotoxic and enteric diseases, including gas gangrene and foodborne or non-foodborne diarrhea. Its control remains challenging due to increasing antimicrobial resistance and the need to preserve beneficial gut microbiota. Here, we identified taxifolin, a naturally occurring flavonoid, as a potential inhibitor of C. perfringens that suppressed its growth and colonization-associated phenotypes while exerting comparatively limited effects on most other tested bacterial species, including commensal bacteria. Proteomic and physiological analyses revealed stress responses associated with iron metabolism, redox balance, and cell division, which were accompanied by reduced mucin adhesion, biofilm formation, and bacterial proliferation. Our findings suggest that taxifolin can reduce the colonization capacity of C. perfringens and support its potential use as a plant-derived approach for limiting C. perfringens intestinal colonization in humans and animals. Clostridium perfringens, a clinically important pathogen in both humans and animals, causes various histotoxic and enteric diseases, including gas gangrene and foodborne or non-foodborne diarrhea. Its control remains challenging due to increasing antimicrobial resistance and the need to preserve beneficial gut microbiota. Here, we identified taxifolin, a naturally occurring flavonoid, as a potential inhibitor of C. perfringens that suppressed its growth and colonization-associated phenotypes while exerting comparatively limited effects on most other tested bacterial species, including commensal bacteria. Proteomic and physiological analyses revealed stress responses associated with iron metabolism, redox balance, and cell division, which were accompanied by reduced mucin adhesion, biofilm formation, and bacterial proliferation. Our findings suggest that taxifolin can reduce the colonization capacity of C. perfringens and support its potential use as a plant-derived approach for limiting C. perfringens intestinal colonization in humans and animals.
Clostridioides difficile is a major cause of antibiotic-associated diarrhea and a significant public health threat. During its infectious cycle, C. difficile encounters various stresses within the gastrointestinal tract. Clp proteases play a crucial role in bacterial stress responses and protein homeostasis. In this study, we investigated the role of the Clp ATPase, ClpC, in C. difficile physiology using genetic, phenotypic, and proteomic analyses. Deletion of clpC reduced heat shock survival but did not affect growth or stationary phase survival under non-stress conditions. Comparative proteomics revealed that ClpC influences the abundance of proteins involved in sporulation, motility, metabolism, and cell wall biosynthesis. The ΔclpC mutant exhibited faster sporulation and increased motility compared to the parental strain. Peptidoglycan quantification showed a significant increase in the ΔclpC mutant, suggesting ClpC's involvement in cell wall homeostasis. The mutant also displayed altered sensitivity to cell wall-targeting antibiotics. Unlike in other bacteria, ClpC did not control the level of MurA, a key enzyme in peptidoglycan precursor synthesis. Instead, the SEDS protein RodA, a transglycosylase involved in peptidoglycan polymerization, accumulated in the ΔclpC mutant. Our findings highlight the pleiotropic role of ClpC in C. difficile, particularly in sporulation, motility, and cell wall metabolism, likely through the degradation of key proteins. Understanding the molecular mechanisms of ClpC-mediated proteolysis in C. difficile stress responses and virulence may provide insights for the development of novel strategies to combat this important pathogen.
Pierre Lacotte, Aurélie Lotoux, Kimberley Casado et al.· Microbial Pathogenesis· 0 citations
BACKGROUND
Quercetin (Que) is widely recognized for its antioxidant and cytoprotective activities, yet its host-directed immunomodulatory mechanisms during Pseudomonas aeruginosa strain UCBPP-PA14 (PA14) infection in the Caenorhabditis elegans model remains insufficiently defined.
PURPOSE
This study examined the protective effects of Que against PA14 and aimed to uncover previously uncharacterized metabolic and signaling mechanisms that contribute to enhanced host defense and epithelial homeostasis.
METHODS
Survival, pharyngeal pumping, intestinal permeability, and PA14 intestinal colonization were assessed, accompanied by antioxidant enzyme profiling, targeted metabolomics of central carbon and glutathione metabolism, and immune-related transcriptional analyses. In vitro antibacterial and antibiofilm activities were also systematically evaluated to distinguish host- from pathogen-directed effects.
RESULTS
Que significantly improved survival, restored pharyngeal pumping, maintained epithelial barrier integrity, and reduced PA14 colonization, whereas only sub-MIC antibiofilm activity with negligible effects on planktonic growth was observed in vitro, indicating a primarily host-centric mode of action. A key innovation of this work is the identification of dose-dependent redox rewiring, characterized by pentose phosphate pathway-glutathione remodeling, elevated NADP⁺, and disrupted GSH/GSSG and NADPH/NADP⁺ ratios. Additionally, Que induced glycolytic redistribution independently of total glucose levels. Transcriptionally, Que suppressed insulin/insulin-like signaling components (daf-2, age-1, pdk-1) and activated daf-16, alongside enhanced sek-1, skn-1, lys-7, and spp-1 expression.
CONCLUSION
These findings reveal a previously unrecognized metabolic-signaling axis through which Que evokes controlled redox perturbation to attenuate IIS, stabilize epithelial physiology, and strengthen antimicrobial defense independently of direct bactericidal effects.
Boya Ouyang, Quanyong Wu, Ze-Bin Zou et al.· Phytomedicine· 0 citations
The antibiotic resistance crisis has become a major threat to global public health. Discovering natural antibacterial compounds with unique mechanisms from traditional medicinal plants is an effective strategy to overcome this challenge. Through activity-guided fractionation, three compounds were isolated from
Turpinia arguta
leaves, identified as piperyamine A, cynaroside, and gallic acid. Cynaroside exhibited the strongest antibacterial activity, with MIC values of 31.25 μg/mL against
Staphylococcus aureus
(Gram-positive) and 62.5 μg/mL against
Vibrio parahaemolyticus
(Gram-negative). Phenotypic experiments, including scanning electron microscopy, electrical conductivity measurements, and alkaline phosphatase (ALP) activity assays, were performed to evaluate antibacterial effects of cynaroside. The results indicated that cynaroside exerted antibacterial effects by disrupting the integrity of bacterial cell walls and cell membranes, with markedly different responses between Gram-positive and Gram-negative bacteria. Specifically, the increase in electrical conductivity was more pronounced in
V. parahaemolyticus
(Gram-negative), while the peak ALP activity was higher in
S. aureus
(Gram-positive). Integrated metabolomic and transcriptomic analyses were conducted to elucidate the differential antibacterial mechanisms. In
S. aureus
, cynaroside treatment was associated with suppression of pyrimidine metabolism and histidine metabolism, negatively regulating 11 metabolites with
pyrC
as the hub gene; in
V. parahaemolyticus
, it mainly inhibited glyoxylate and dicarboxylate metabolism and branched-chain amino acid degradation, negatively regulating tricarboxylic acid cycle intermediates with
fdh3B
as the hub gene. This study reveals the differential antibacterial mechanisms of cynaroside isolated from
Turpinia arguta
against Gram-positive and Gram-negative bacteria, laying a theoretical foundation for the development of species-selective natural antibacterial agents.
Shi-Qi Xia, Daofeng Liu, Hao-Wen Zhang et al.· Frontiers in Microbiology· 0 citations
Acne vulgaris is a chronic inflammatory skin disorder in which Cutibacterium acnes contributes to disease persistence through biofilm formation, lipid metabolism, and production of inflammatory metabolites within the pilosebaceous unit. Targeting bacterial physiological pathways that sustain these processes represents a potential therapeutic strategy beyond conventional antibiotic approaches. In this study, we evaluated a panel of halogenated indole derivatives and identified 6-bromo-4-iodoindole as a potent inhibitor of C. acnes growth and biofilm formation. The compound exhibited a minimum inhibitory concentration of 20 μg/mL and disrupted biofilm architecture. Further analyses revealed that treatment markedly altered several virulence-associated phenotypes, including reductions in extracellular lipase activity, cell-surface hydrophobicity, extracellular polymeric substance production, and porphyrin levels, accompanied by increased intracellular reactive oxygen species. Because lipase activity plays a central role in sebum metabolism and follicular colonization by C. acnes, molecular docking was performed to evaluate potential target engagement. Docking simulations suggested that 6-bromo-4-iodoindole occupies the catalytic pocket of C. acnes triacylglycerol lipase, providing a structural basis for the observed suppression of lipase-dependent phenotypes. Importantly, the compound retained biofilm inhibitory activity in polymicrobial C. acnes + Staphylococcus aureus biofilms, exhibited broad-spectrum growth inhibition extending to S. epidermidis, and significantly reduced bacterial recovery in an ex vivo porcine skin model. In silico pharmacokinetic analyses further indicated physicochemical properties compatible with localized topical delivery. Together, these findings demonstrate that a dihalogenated indole reduces lipase-associated virulence related phenotypes in C. acnes and suppresses biofilm formation in skin-relevant environments, supporting further investigation of this scaffold as a therapeutic strategy targeting acne-associated microbial physiology.
S. Angulmaduwa, G.G. Roshan Pradeep Ratupaskatiye, Yong-Guy Kim et al.· Microbial Pathogenesis· 0 citations
Findings underscore a significant role for VdOMO in siderophore-associated iron acquisition, fungal development, stress adaptation, and the early stages of host colonization in V. dahliae.
Yusha Du, Lixinyu Sun, Kang-Wei Xie et al.· Frontiers in Plant Science· 0 citations
The integrated experimental and in silico approach highlights soil-derived actinomycetes as versatile and sustainable bioresources with significant pharmaceutical and biotechnological potential, emphasizing their role in combating antimicrobial resistance and enabling the rational development of novel therapeutic and industrial products.
Meghana Arivilu, Shaziya Sulthana, Vijay Ramesh et al.· Journal of Pure and Applied...· 0 citations
