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Electrostatic Trojan Horse: Charge-Anchored Pleuromutilin Breaches Anionic Barriers to Hijack Ribosomes in Antibiotic-Resistant Bacteria. 静电特洛伊木马:带电荷的胸膜残蛋白破坏了耐药细菌中劫持核糖体的阴离子屏障。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-07 DOI: 10.1021/acsinfecdis.5c01027
Lei Tian, Boxin Zhang, Bingxing Zhang, Jinrong Hu, Changhua Ke, Yunfei Zhang, Jingjing Zhou, Hui Xiong, Juan Xia, Jiang Nan, Mengzhou Wang, Zhiyou Yang, Bin Tian, Qianqian Zhao, Wenliang Wang, Xu Zhao, Taotao Qiang, Chengyuan Liang

Antimicrobial resistance threatens health, and new agents are needed. Lefamulin is the only approved antibiotic of a new class in two decades. It targets the 50S peptidyl transferase center (PTC). Its efficacy against multidrug-resistant pathogens is limited by anionic envelopes, limiting penetration. We report a charge-anchored pleuromutilin exploiting an electrostatic Trojan horse to breach barriers and engage the ribosome. An N-pyridinium provides a cationic localizer. A two-step mechanism operates. Long-range electrostatics enrich ligands at anionic interfaces and the PTC. Short-range interactions secure high-affinity placement of the tricyclic core. Computer simulations support the occupancy of the activity pocket and the field-guided orientation of the cationic side chain for PNY-6b. Proteomics highlights ribosomal proteins as dominant targets. Cellular assays show biofilm eradication and membrane depolarization. In murine infections, PNY-6b lowers burden and improves survival. Electrostatic complementarity offers a generalizable design principle for targets with electrostatic fields and for pathogens with poor envelope permeability.

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引用次数: 0
Trained Immunity Empowers Vaccine Design and Application. 训练有素的免疫能力增强了疫苗的设计和应用。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-07 DOI: 10.1021/acsinfecdis.5c00840
Qijun Hu, Zibo Mai, Bosen Wang, Ning Sun, Wenjuan Zhu, Jiaqing Wang, Junwei Ge, Mingchun Gao

The COVID-19 pandemic has exposed the limitations of traditional vaccine development models: these approaches rely excessively on pathogen-specific antigen design, feature lengthy development cycles, and struggle to address threats from rapidly mutating pathogens and emerging pathogens. Even before the pandemic, certain traditional vaccines (such as BCG) demonstrated "cross-protection" effects beyond their target diseases. The trained immunity (TRIM) theory offers a promising path to develop broad-spectrum, effective, and durable vaccines. This review summarizes core advances in TRIM within vaccinology, systematically outlining vaccine design strategies based on this concept for the first time. These strategies encompass vaccine-mediated cross-protection, methods to enhance vaccine potency and persistence, pathways to achieve broad-spectrum effects, and regulatory characteristics involving immune recognition, antigen delivery, safety, and tolerability. This study explores the synergistic effects and application prospects of TRIM adjuvants such as β-glucan and Toll-like receptor (TLR) agonists. The impact of transgenerational immune effects on offspring immune function provides a crucial direction for future research. It also highlights current limitations in studies regarding persistence, individual variability, and risks of excessive inflammation. Existing vaccines capable of inducing TRIM will inspire next-generation vaccine development. Innovative applications of this vaccine category can propel the advancement of trained immunity-based vaccines (TIbVs). This review proposes an innovative approach─the "Vaccine Immunity Foundation Hypothesis." This lays the groundwork for designing next-generation vaccines and advancing the clinical translation of TRIM therapies, establishing a theoretical foundation for developing broad-spectrum, highly effective, durable, and safe immune protection strategies.

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引用次数: 0
Targeted Neutrophil Extracellular Traps Mimics Combat Staphylococcus aureus Infections. 靶向中性粒细胞胞外诱捕模拟物对抗金黄色葡萄球菌感染。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-05 DOI: 10.1021/acsinfecdis.5c00831
Zhuo-Yue Li, Shao-Yu Hu, Guo-Yang Xu, Jing-Xian Huang, Xi-You Yang, Tian-Ci Wei, Jia-Qi Feng, Jun-Xiao Yuan, Chao-Ran Li, Yu-Ting Li, Jie Weng, Xu Cui, Hao Wang, Qiong Nie, Lei Wang, Li-Tao Li

Neutrophil extracellular traps (NETs) are crucial innate immune components that ensnare and neutralize pathogens. Inspired by this, we engineered a novel peptide, RFC, designed to mimic NETs' "trap-and-kill" strategy against Staphylococcus aureus infections. RFC integrates an antimicrobial peptide (KR12), a self-assembling motif (KLVFF), and a Staphylococcus-targeting sequence (CARGGLKSC). In vitro, RFC exhibited potent broad-spectrum activity (minimum inhibitory concentration (MIC) as low as 4 μM), fast bactericidal kinetics (>3-log10 reduction within 2 h at 1× MIC), inhibited biofilm formation (>92% at 2× MIC), and eradicated persister cells, while showing high biocompatibility. RFC self-assembles into nanofibrillar networks for bacterial entrapment and disrupts membranes. In vivo, RFC potently treated murine polymicrobial skin infections (99.3% wound closure) and lethal sepsis, improving survival from 16.6% to 66.7%, clearing bacteremia, and suppressing cytokines without toxicity. These findings highlight RFC as a promising antimicrobial agent, combining bacterial targeting, killing, and aggregation with tissue healing and immune activation capabilities, offering a novel strategy against challenging S. aureus infections.

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引用次数: 0
Antifungal Activity of Lipophilic Bisphosphonates. 亲脂性双磷酸盐的抗真菌活性。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 10.1021/acsinfecdis.5c00838
Akanksha M Pandey, Ruijie Zhou, Davinder Singh, Fangrong Li, Mingdi He, Annie Le, Jayannah Herdrich, Yiyuan Chen, Rishi Shah, Serwa Adusei-Poku, Nicholas J Rohlwing, Jamie Koo, Zi Ying Ong, Eric Oldfield

We investigated the activity of a series of 75 lipophilic bisphosphonates against Candida glabrata. Thirty-six compounds had MIC < 1 μg/mL, 18 had MIC < 0.5 μg/mL, and 2 had MIC = 0.13 μg/mL, comparable to amphotericin B and caspofungin. The lipophilic bisphosphonates were ∼20-fold more potent against C. glabrata than the most potent hydrophilic bisphosphonate, zoledronate. The most active compounds were pyridinium bisphosphonates followed by imidazolium bisphosphonates, while aryl bisphosphonates were less active. Several compounds had selectivity index values against a human cell line in the 1000-3600 range, the most selective compounds being para-substituted pyridinium bisphosphonates. We also found similar activity against a caspofungin-resistant FKS2 (F659S) mutant. Some combinations of lipophilic bisphosphonates had synergistic activity with FICI values in the ∼0.3-0.5 range, and similar synergies were observed with fluconazole, implicating ergosterol biosynthesis inhibition leading to compromised membrane structure and function. Cell growth inhibition was rescued by ascorbic acid, glutathione, and N-acetyl cysteine, indicating a ROS-based killing mechanism. There was also synergy with other antifungals but very strong antagonism with verapamil (FICI ∼4), which blocks calcium channels. Unlike hydrophilic bisphosphonates, which target farnesyl diphosphate synthase, lipophilic bisphosphonates also target squalene synthase, suggesting that the combination of multitargeting bisphosphonates is one origin of the synergistic interactions observed. Given that one of the lipophilic bisphosphonates studied here (BPH-1237) has been shown to have activity against many other human fungal pathogens, combinations with the compounds described here may be of interest as antifungal leads.

我们研究了一系列75种亲脂双膦酸盐对光滑假丝酵母的活性。MIC < 1 μg/mL的化合物有36个,MIC < 0.5 μg/mL的有18个,MIC = 0.13 μg/mL的有2个,与两性霉素B和卡泊芬金相当。亲脂性双膦酸盐对光棘球蛾的效力是最有效的亲水双膦酸盐唑来膦酸盐的20倍。活性最高的化合物是二膦酸吡啶,其次是咪唑二膦酸酯,而芳基二膦酸酯活性较低。几种化合物对人细胞系的选择性指数在1000-3600范围内,选择性最高的化合物是对取代双膦酸吡啶。我们还发现对caspofunins抗性FKS2 (F659S)突变体具有类似的活性。一些亲脂双膦酸盐组合与FICI值在0.3-0.5范围内具有协同作用,与氟康唑也观察到类似的协同作用,这意味着麦角甾醇生物合成抑制导致膜结构和功能受损。细胞生长抑制被抗坏血酸、谷胱甘肽和n -乙酰半胱氨酸恢复,表明基于ros的杀伤机制。与其他抗真菌药物也有协同作用,但与阻断钙通道的维拉帕米(FICI ~ 4)有很强的拮抗作用。与以法尼基二磷酸合成酶为靶点的亲水双磷酸盐不同,亲脂双磷酸盐也以角鲨烯合成酶为靶点,这表明多靶点双磷酸盐的组合是所观察到的协同相互作用的一个来源。鉴于本文研究的一种亲脂性双膦酸盐(BPH-1237)已被证明对许多其他人类真菌病原体具有活性,因此与本文所述化合物的组合可能会成为抗真菌的线索。
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引用次数: 0
Construction and Activity Evaluation of Biphenyl Hydroxamic Acid Dual-Target Antibacterial Inhibitor and Nanocarrier. 联苯羟肟酸双靶点抗菌抑制剂及纳米载体的构建及活性评价。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-04 DOI: 10.1021/acsinfecdis.5c00928
Shiying Zhang, Anli Zhang, Shuai Yu, Yating Liu, Bin Sun

Gram-negative bacterial infections are characterized by the release of lipopolysaccharide (LPS), a key outer membrane component that triggers a robust host immune response via TLR4 signaling. In this study, three series of dual-target (LpxC/PD-L1) inhibitors were rationally designed via a structural splicing approach, synthesized, and evaluated for their in vitro biological activities. Among them, compound 12d displayed potent antibacterial activity and significant dual-target (LpxC/PD-L1) inhibitory efficacy. To improve its bioavailability and targeting capability, the nanocomposite (NC-12d) was further constructed to sense the infection microenvironment. Subsequent in vivo evaluation confirmed the dual therapeutic functions of these agents: effective bacterial suppression and immune activation, which collectively accelerated host recovery from drug-resistant bacterial infection. In summary, this study not only broadens the scope of antibacterial drug development but also offers a drug delivery pathway for the treatment of bacterial infections.

革兰氏阴性细菌感染的特征是脂多糖(LPS)的释放,脂多糖是一种关键的外膜成分,通过TLR4信号触发宿主强烈的免疫反应。本研究通过结构剪接的方法合理设计了三个系列的双靶点(LpxC/PD-L1)抑制剂,并进行了合成,并对其体外生物活性进行了评价。其中,化合物12d表现出较强的抑菌活性和显著的双靶点(LpxC/PD-L1)抑制作用。为了提高其生物利用度和靶向性,进一步构建纳米复合材料(NC-12d)来感知感染微环境。随后的体内评估证实了这些药物的双重治疗功能:有效的细菌抑制和免疫激活,它们共同加速了宿主从耐药细菌感染中恢复。综上所述,本研究不仅拓宽了抗菌药物的开发范围,也为治疗细菌感染提供了一种药物传递途径。
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引用次数: 0
β-Hairpin Antimicrobial Peptides: Class Diversity and Sequence Analysis. β-发夹抗菌肽的分类多样性和序列分析。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-02-02 DOI: 10.1021/acsinfecdis.5c01055
Rabina Ramtel, Richard Gu, Mutiat A Abdulkareem, Justin R Randall

Interest in antimicrobial peptides has increased dramatically over the last few decades as researchers continue to explore their potential as alternatives to small molecules, as well as their applications in agriculture and food preservation. One promising yet small antimicrobial peptide class is that consisting of a single β-hairpin cyclized via intramolecular disulfide bonds, commonly termed β-hairpin antimicrobial peptides (β-AMPs). Their short length constrained cyclic structure and wide range of activities make them exciting to the general scientific community and drug developers alike; however, despite being found across several phyla, there remain fewer than 30 identified sequence families, making them exceedingly rare relative to more common structural classes. In this review, we identify and describe 27 unique macrocyclic β-AMP sequence families from the literature, with an emphasis on newer and lesser-known families. We then analyze the class's sequence composition both as a whole and broken down by structural region, finding common characteristics including lengths of 11-25 amino acids, cationic charge, two or more cysteine pairs separated by at least three residues, and strong enrichment for arginine relative to lysine. We then discuss strategies for using these sequence characteristics to help expand the class and improve their relative underrepresentation.

在过去的几十年里,随着研究人员不断探索抗菌肽作为小分子替代品的潜力,以及它们在农业和食品保鲜中的应用,人们对抗菌肽的兴趣急剧增加。一种很有前景的小型抗菌肽是由一个通过分子内二硫键环化的β-发夹组成的,通常被称为β-发夹抗菌肽(β- amp)。它们的短长度约束循环结构和广泛的活动范围使它们对一般科学界和药物开发人员都很兴奋;然而,尽管在几个门中被发现,但仍然只有不到30个已确定的序列家族,这使得它们相对于更常见的结构类来说非常罕见。在这篇综述中,我们从文献中鉴定和描述了27个独特的大环β-AMP序列家族,重点是较新的和鲜为人知的家族。然后,我们分析了这一类的序列组成,无论是作为一个整体还是按结构区域分解,发现了共同的特征,包括11-25个氨基酸的长度,阳离子电荷,两个或更多的半胱氨酸对被至少三个残基分开,以及精氨酸相对于赖氨酸的强富集。然后,我们讨论了使用这些序列特征来帮助扩展类并改善其相对代表性不足的策略。
{"title":"β-Hairpin Antimicrobial Peptides: Class Diversity and Sequence Analysis.","authors":"Rabina Ramtel, Richard Gu, Mutiat A Abdulkareem, Justin R Randall","doi":"10.1021/acsinfecdis.5c01055","DOIUrl":"10.1021/acsinfecdis.5c01055","url":null,"abstract":"<p><p>Interest in antimicrobial peptides has increased dramatically over the last few decades as researchers continue to explore their potential as alternatives to small molecules, as well as their applications in agriculture and food preservation. One promising yet small antimicrobial peptide class is that consisting of a single β-hairpin cyclized via intramolecular disulfide bonds, commonly termed β-hairpin antimicrobial peptides (β-AMPs). Their short length constrained cyclic structure and wide range of activities make them exciting to the general scientific community and drug developers alike; however, despite being found across several phyla, there remain fewer than 30 identified sequence families, making them exceedingly rare relative to more common structural classes. In this review, we identify and describe 27 unique macrocyclic β-AMP sequence families from the literature, with an emphasis on newer and lesser-known families. We then analyze the class's sequence composition both as a whole and broken down by structural region, finding common characteristics including lengths of 11-25 amino acids, cationic charge, two or more cysteine pairs separated by at least three residues, and strong enrichment for arginine relative to lysine. We then discuss strategies for using these sequence characteristics to help expand the class and improve their relative underrepresentation.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural Analysis of 23S rRNA Methylating Enzyme Cfr Reveals RNA-Binding Determinants for Methylation Regiospecificity and Antibiotic Resistance. 23S rRNA甲基化酶Cfr的结构分析揭示了甲基化区域特异性和抗生素耐药性的rna结合决定因素。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-01-30 DOI: 10.1021/acsinfecdis.5c00828
Michael Fruci, Annia Rodríguez Hernández, Tatiana Skarina, Lou Ann Verellen, Kaitlyn Tsai, Johanna M Virta, Danica Galonić Fujimori, Alexei Savchenko, Peter J Stogios

The 23S rRNA methylating enzyme Cfr, found in pathogens including Staphylococcus aureus, Clostridium difficile, Escherichia coli, and Klebsiella pneumoniae, confers resistance to phenicols, lincosamides, oxazolidinones (including linezolid), pleuromutilins, and streptogramins A (the PhLOPSA phenotype). Cfr catalyzes methylation of the C8 position of the A2503 base in 23S rRNA, the recognition site of the above antibiotic classes. Along with the RlmN housekeeping enzyme, Cfr can also promote methylation of the C2 position of the same base. The molecular and structural basis of Cfr's dual substrate specificity is not known, which hinders our ability to design Cfr-targeting inhibitors necessary to curb PhLOPSA resistance. Here, we present the first crystal structure of Cfr and a detailed analysis of its possible interactions with rRNA. Using structure-guided mutagenesis, mass spectrometry analysis of in cellulo 23S rRNA methylated species, and in cellulo resistance studies, we identify the key amino acids essential for Cfr methylation and multidrug resistance activity. In particular, we found that Cfr's Q329 residue is important for C8-specific methylation. These data provide a framework for further studies of the biochemistry, structure, and inhibition of this important resistance determinant.

在包括金黄色葡萄球菌、艰难梭菌、大肠杆菌和肺炎克雷伯菌在内的病原体中发现的23S rRNA甲基化酶Cfr,赋予对酚类、lincosamides、恶唑烷酮(包括利奈唑胺)、胸膜多素和链状gramins A (PhLOPSA表型)的耐药性。Cfr催化23S rRNA中A2503碱基C8位点的甲基化,这是上述抗生素类别的识别位点。与RlmN管家酶一起,Cfr也能促进同一碱基C2位置的甲基化。Cfr双底物特异性的分子和结构基础尚不清楚,这阻碍了我们设计抑制PhLOPSA耐药所需的Cfr靶向抑制剂的能力。在这里,我们提出了Cfr的第一个晶体结构,并详细分析了它与rRNA可能的相互作用。利用结构导向诱变、质谱分析celllo 23S rRNA甲基化物种以及在celllo耐药研究中,我们确定了Cfr甲基化和多药耐药活性所必需的关键氨基酸。特别是,我们发现Cfr的Q329残基对c8特异性甲基化很重要。这些数据为进一步研究这一重要抗性决定因素的生物化学、结构和抑制作用提供了框架。
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引用次数: 0
The Pyridoxal-5'-Phosphate-Dependent Enzymes of Mycobacterium tuberculosis. 结核分枝杆菌吡哆醛-5′-磷酸依赖酶的研究。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-01-30 DOI: 10.1021/acsinfecdis.5c00996
Alessio Peracchi, Bienyameen Baker

Enzymes that depend on the cofactor pyridoxal 5'-phosphate (PLP) catalyze a remarkable variety of biochemical reactions in all organisms. In particular, the genome of Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), encodes 45 bona fide PLP-dependent enzymes plus a few related proteins that presumably do not have enzymic function. The large majority of the 45 enzymes have been characterized in terms of catalytic activity and structure. Several of them have been shown to be central to the bacterium's survival and pathogenicity, while some of these enzymes are targets of an extant drug (d-cycloserine). Herein, the annotated catalog of the PLP-dependent enzymes in M. tuberculosis is presented and analyzed with three main goals in mind. The first will be to assess the specific aspects of mycobacterial metabolism that rely most on PLP-dependent enzymes. A second goal will be to signal those enzymes whose function is still uncertain and whose functional characterization may help to further understand the biology of M. tuberculosis. Finally, we will examine the potential and limitations of targeting the PLP-dependent enzymes for the development of new antimycobacterial drugs.

依赖于辅因子吡哆醛5'-磷酸(PLP)的酶在所有生物体中催化各种显著的生化反应。特别是,结核病(TB)的病原体结核分枝杆菌的基因组编码45种真正的plp依赖性酶和一些可能不具有酶功能的相关蛋白。在这45种酶中,绝大多数都已根据催化活性和结构进行了表征。其中一些酶已被证明对细菌的生存和致病性至关重要,而其中一些酶是现有药物(d-环丝氨酸)的靶标。本文介绍了结核分枝杆菌中plp依赖性酶的注释目录,并分析了三个主要目标。首先是评估分枝杆菌代谢中最依赖plp依赖性酶的具体方面。第二个目标将是向那些功能仍不确定的酶发出信号,这些酶的功能特征可能有助于进一步了解结核分枝杆菌的生物学。最后,我们将研究针对plp依赖性酶开发新的抗细菌药物的潜力和局限性。
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引用次数: 0
Identification of G-Quadruplexes in Hepatitis E Virus Negative-Sense Genomic RNA as Potent Antiviral Targets. 戊型肝炎病毒负义基因组RNA中g -四联体作为有效抗病毒靶点的鉴定
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-01-28 DOI: 10.1021/acsinfecdis.5c01069
Xiaohui Ding, Dou Zeng, Yingying Bian, Dan Liu, Qiudi Li, Ruilin Si, Yunlu Sha, Huiyuan Fu, Ying Li, Xutong Ding, Xueting Liu, Nannan Li, Shiquan Liang, Yibo Ding, Wenshi Wang, Hongbo Guo

Hepatitis E virus (HEV) causes significant global disease burden with no approved targeted therapies, highlighting the urgent need for innovative treatment strategies. G-quadruplexes (G4s), noncanonical nucleic acid structures formed by guanine-rich sequences, have emerged as important regulators of viral replication. Here, we identified two potential G4 sequences within HEV negative-sense genomic RNA. Circular dichroism spectroscopy confirmed their stable, parallel G4 structures, with structural stability enhanced by the G4-binding ligand pyridostatin (PDS). Using an EGFP reporter system, we demonstrated that these G4s significantly suppressed downstream gene expression, an effect potentiated by PDS treatment. In HEV infection models, PDS substantially inhibited viral RNA synthesis and ORF2 protein expression. This antiviral activity was recapitulated by the structurally distinct G4-binding ligand TMPyP4, but not by the weak-binding control TMPyP2, confirming G4-dependent regulation. Our findings establish G4s as functional regulatory elements in the HEV life cycle and as promising RNA-targeted therapeutic targets against HEV.

戊型肝炎病毒(HEV)造成了重大的全球疾病负担,目前尚无获批的靶向治疗方法,这凸显了对创新治疗策略的迫切需求。g -四联体(G4s)是由富含鸟嘌呤序列形成的非典型核酸结构,已成为病毒复制的重要调节因子。在这里,我们在HEV负义基因组RNA中鉴定了两个潜在的G4序列。圆二色光谱证实了它们稳定、平行的G4结构,并通过G4结合配体pyridostatin (PDS)增强了结构稳定性。使用EGFP报告系统,我们证明这些G4s显著抑制下游基因表达,PDS处理增强了这一作用。在HEV感染模型中,PDS显著抑制病毒RNA合成和ORF2蛋白表达。这种抗病毒活性是由结构独特的g4结合配体TMPyP4再现的,但不是由弱结合对照TMPyP2再现的,证实了g4依赖性调控。我们的研究结果表明G4s是HEV生命周期中的功能调控元件,也是一种有希望的rna靶向治疗HEV的靶点。
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引用次数: 0
Modeling and Functional Characterization of Reconstituted Efflux Pump Components from Heterologous Gram-Negative Bacteria. 异种革兰氏阴性菌重组外排泵组件的建模和功能表征。
IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2026-01-28 DOI: 10.1021/acsinfecdis.5c00612
Purnendu Bhowmik, Anirudh P Shanbhag, Suryanarayanan Venkatesan, Nagakumar Bharatham, Santanu Datta, Vasanthi Ramachandran

Efflux pumps operating in bacteria continuously evolve and contribute significantly toward the rising global trends in antimicrobial resistance (AMR). Our earlier studies demonstrated that the expression of tripartite resistance nodulation division (RND) efflux pump containing the outer membrane protein (OMP), membrane fusion protein (MFP), and inner RND pump from different Gram-negative bacteria results in elevated minimum inhibitory concentrations (MICs) of different antibiotics. Interestingly, parts of this complex could be transferred either within the species or across genera. Despite limited sequence homology, we report the existence of significant structural and functional conservation between the distantly related MFP and RND proteins. Following the assembly of MFP components (AcrA, MexA, OqxA) and RND components (AcrB, MexB, OqxB) from E. coli, P. aeruginosa, and K. pneumoniae, respectively, we report evidence of functioning efflux pumps using real-time Nile Red assays and enhanced biofilm formation. Further substantiation of the latter is provided through docking and molecular dynamics (MD) simulation studies, which offer insights about the direct interactions of RND efflux pumps with AI-2, the major quorum-sensing molecule of E. coli. Results described here implicate that after transmission, possibly via horizontal gene transfer or e-DNA within bacteria, the assembled efflux pump components could drive multiple aspects of AMR, including its dissemination and ability to adapt to alternate lifestyles such as biofilms, facilitating better survival.

在细菌中运行的外排泵不断发展,并对抗菌素耐药性(AMR)的全球趋势上升做出了重大贡献。我们早期的研究表明,不同革兰氏阴性菌中含有外膜蛋白(OMP)、膜融合蛋白(MFP)和内膜融合蛋白的三部耐药结瘤分裂(RND)外排泵的表达可导致不同抗生素的最低抑制浓度(mic)升高。有趣的是,这种复合物的一部分可以在物种内或跨属转移。尽管序列同源性有限,但我们报告了远亲MFP和RND蛋白之间存在显着的结构和功能守恒。在分别组装来自大肠杆菌、铜绿假单胞菌和肺炎克雷伯菌的MFP组分(AcrA、MexA、OqxA)和RND组分(AcrB、MexB、OqxB)之后,我们使用实时尼罗红测定和增强的生物膜形成报告了功能外排泵的证据。通过对接和分子动力学(MD)模拟研究进一步证实了后者,这些研究提供了RND外排泵与大肠杆菌主要群体感应分子AI-2的直接相互作用的见解。本研究的结果表明,在传播后,可能通过水平基因转移或细菌内的e-DNA,组装的外排泵组件可以驱动AMR的多个方面,包括其传播和适应替代生活方式(如生物膜)的能力,从而促进更好的生存。
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引用次数: 0
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