Nature Communications
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2025
·Vol. 16
·期 1
·1-14
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IF 15.7
He Wenyan,Huan Xueting,Li Yinchuan,Deng Qisen,Chen Tao,Xiao Wen,Chen Yijun,Ma Lingman,Liu Nan,Shang Zhuo,Wang Zongqiang
The rapid emergence of difficult-to-treat multidrug-resistant pathogens, combined with the scarcity of antibiotics possessing novel mechanisms, poses a significant threat to global public health. Here, we integrate the synthetic-bioinformatic natural product approach with peptide optimization to unveil the antibiotic-producing potential of Paenibacillaceae bacteria. Our culture-independent approach led to the discovery of paenimicin, a novel 11-mer depsi -lipopeptide featuring an unprecedented dual-binding mechanism. By sequestering the phosphate and hydroxyl groups of lipid A in Gram-negative bacteria, as well as the phosphate groups of teichoic acids in Gram-positive bacteria, paenimicin exhibits potent and broad-spectrum efficacy against MDR pathogens in vitro and in vivo models. Paenimicin demonstrates no detectable resistance, favorable pharmacokinetics and low nephrotoxicity, positioning it as a promising candidate for treating severe and urgent MDR infections.
研究领域:
抗菌研究
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生物信息学
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微生物学
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药理学
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传染病学
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合成生物学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2025
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IF 5.7
Meng Fang,Liping Lin,Lvjuan Lin,Yaojia Lin,Muyue Zheng,Jinye Zhang,Wei Liu,Qitong Huang
The escalating prevalence of multidrug-resistant Gram-positive bacterial infections demands the development of antimicrobial agents with precise targeting and rapid bactericidal activity. In this study, ultra-small positively-charged carbon dots (PR-CDs) were synthesized through a one-step hydrothermal synthesis of polyethyleneimine and Rhodamine B. The resulting PR-CDs exhibited multiple antibacterial mechanisms: (1) electrostatic attraction to Gram-positive bacterial membranes, (2) cellular internalization enabled by their ultra-small size (2.3 nm), and (3) visible light-activated reactive oxygen species (ROS) generation. PR-CDs have shown selective bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive pathogens with minimum bactericidal concentrations as low as 19.53 μg mL−1 under light irradiation. Mechanistic studies revealed that the positive charges on the surface of PR-CDs facilitated selective binding to teichoic acid-rich Gram-positive cell walls, while their nanoscale dimensions permitted deep penetration into bacterial cells, enhancing oxidative damage through rapid generation of singlet oxygen (1O2). Encapsulation of PR-CDs in gellan gum (PR-CDs@GG) hydrogels enabled sustained ROS release and accelerated MRSA-infected wound healing in MRSA-infected mice, achieving 82.51% wound closure within 8 days without systemic toxicity. This work establishes a paradigm for precision antimicrobial design via integrating targeted binding, cellular penetration, and photodynamic activation.
研究领域:
纳米技术
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抗菌剂
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光动力疗法
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生物医学工程
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伤口愈合
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微生物学
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材料科学
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DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Lu Yunfu,Chen Feifei,Zhao Qingmin,Cao Qiao,Chen Rongrong,Pan Huiwen,Wang Yanhui,Huang Haixin,Huang Ruimin,Liu Qian,Li Min,Bae Taeok,Liang Haihua,Lan Lefu
Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator ( agr ) locus and spa . The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus .
研究领域:
微生物学
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分子生物学
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传染病学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
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2023
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IF 6.5
Hong Zhou,Xi Tan,Guozhong Chen,Xinxin Liu,Aiping Feng,Zhi Liu,Wei Liu
Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder in which the skin is affected by microbial dysbiosis . The role of commensal skin microbiota in AD is of great interest. Extracellular vesicles (EVs) are important regulators of skin homeostasis and pathology. The mechanism of preventing AD pathogenesis through commensal skin microbiota–derived EVs remains poorly understood. In this study, we investigated the role of commensal skin bacterium Staphylococcus epidermidis– derived EVs (SE-EVs). We showed that SE-EVs significantly decreased the expression of proinflammatory genes ( TNFα , IL1β , IL6 , IL8 , and iNOS ) through lipoteichoic acid and increased the proliferation and migration of calcipotriene (MC903)-treated HaCaT cells. Furthermore, SE-EVs increased the expression of human β-defensins 2 and 3 in MC903-treated HaCaT cells through toll-like receptor 2, enhancing resistance to S. aureus growth. In addition, topical SE-EV application remarkably attenuated inflammatory cell infiltration (CD4 + T cells and Gr1 + cells), T helper 2 cytokine gene expression ( Il4 , Il13 , and Tlsp ), and IgE levels in MC903-induced AD-like dermatitis mice. Intriguingly, SE-EVs induced IL-17A + CD8 + T-cell accumulation in the epidermis, which may represent heterologous protection. Taken together, our findings showed that SE-EVs reduced AD-like skin inflammation in mice and may potentially be a bioactive nanocarrier for the treatment of AD.
研究领域:
皮肤科
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免疫学
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微生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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