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更新于：2025-05-07

WalK

更新于：2025-05-07

基本信息

别名

Sensor histidine kinase WalK

简介

Member of the two-component regulatory system WalK/WalR that regulates genes involved in cell wall metabolism, virulence regulation, biofilm production, oxidative stress resistance and antibiotic resistance via direct or indirect regulation of autolysins (PubMed:14762013, PubMed:17827301, PubMed:22825451). Functions as a sensor protein kinase which is autophosphorylated at a histidine residue in the dimerization domain and transfers its phosphate group to the conserved aspartic acid residue in the regulatory domain of WalR. In turn, WalR binds to the upstream promoter regions of the target genes to positively and negatively regulate their expression (PubMed:14762013, PubMed:22825451).

关联

项与 WalK 相关的药物

Signermycin B

靶点

WalK

作用机制

Walk蛋白抑制剂

在研机构

Kinki University

原研机构

Kinki University

在研适应症

革兰氏阳性细菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

WalK activator(Jinan University)

靶点

WalK

作用机制

Walk蛋白激活剂

在研机构

暨南大学

原研机构

暨南大学

在研适应症

耐甲氧西林金黄色葡萄球菌感染

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

Walkmycin C

靶点

WalK

作用机制

Walk蛋白抑制剂

在研机构-

原研机构

Kinki University

在研适应症-

非在研适应症

变形菌感染

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 WalK 相关的临床结果

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100 项与 WalK 相关的转化医学

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0 项与 WalK 相关的专利（医药）

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110

项与 WalK 相关的文献（医药）

2025-04-02·Journal of Antimicrobial Chemotherapy

Simulated exposures of oritavancin in in vitro pharmacodynamic models select for methicillin-resistant Staphylococcus aureus with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials

Article

作者: Werth, Brian J ; Waalkes, Adam ; Salipante, Stephen J ; Barreras Beltran, Ismael A ; Penewit, Kelsi ; Xu, Libin ; Holmes, Elizabeth A ; Zhang, Rutan

AbstractBackgroundDalbavancin exposures select for VAN and daptomycin cross-resistance in Staphylococcus aureus often by walK-related mutations. Oritavancin is another long-acting lipoglycopeptide, but its proclivity to select for cross-resistance is unknown. The objective of this study was to determine if post-distributional pharmacokinetic oritavancin exposures select for meaningful susceptibility changes in S. aureus.MethodsWe simulated average post-distributional, free-drug exposures of oritavancin 1200 mg IV once (fCmax 11.2 µg/mL; β-elimination t1/2 13.4 h; γ-elimination t1/2 245 h) in an in vitro pharmacodynamic model for 28 days against five S. aureus including four MRSA. Samples were taken daily for colony enumeration and resistance screening. Susceptibility testing was repeated on isolates from resistance screening plates against oritavancin, vancomycin, daptomycin, dalbavancin and 6 beta-lactams with varying penicillin-binding protein affinities.ResultsTested oritavancin exposures were bactericidal against 5/5 strains for 2–17 days before regrowth of less-susceptible subpopulations occurred. Isolates with reduced susceptibility to oritavancin were detected as early as 5 days, but the MIC increased above the susceptibility breakpoint (>0.125 mg/L) in 4/5 strains eventually. Vancomycin and daptomycin MICs increased by 2- to 8-fold but did not exceed the susceptibility breakpoints in most isolates. β-lactam MICs were largely unchanged among the recovered isolates with reduced oritavancin susceptibility. Mutations were diverse but often involved purR with 13 unique variants identified among 4/5 strains.ConclusionsOritavancin-selected resistance was primarily associated with purR mutation and less frequently associated with cross-resistance and walK mutation than dalbavancin-selected resistance in similar strains and conditions. The reason for this is unclear but may stem from differences in the mechanism(s) and divergent mutational pathways.

2025-03-01·Environment International

Emerging threat to antibiotic resistance: Impact of mycotoxin deoxynivalenol on gut microbiota and clonal expansion of extensively drug-resistant enterococci

Article

作者: Deng, Yiqun ; Ke, Linyu ; Chen, Meichan ; Deng, Fengru ; Yao, Chuying ; Chen, Qingmei ; Wen, Jikai ; Jiang, Jun ; Huang, Mi

Mycotoxins, antibiotic-resistant bacteria (ARB), and antibiotic resistance genes (ARGs) are significant environmental pollutants that pose considerable threats to environmental health and human safety through the food chain. This study is the first to investigate the impact of deoxynivalenol (DON), the most common mycotoxin, on antibiotic resistance dynamics in gut microbiota, demonstrating that DON exposure significantly selects for ARB and ARGs. Results indicated that 80.69 % of the ARGs with the highest increase in the DON group were exclusive to gram-positive bacteria, particularly those related to daptomycin. DON exposure enhanced the expression of virulence factors in gram-positive bacteria and increased reactive oxygen species (ROS) production and membrane permeability, compromising bacterial integrity and amplifying resistance mechanisms. DON also boosted the diversity and co-occurrence of ARGs and mobile genetic elements (MGEs), potentially facilitating the horizontal transfer of resistance traits. Notably, the dominant bacterial species isolated from broiler gut microbiota was identified as Enterococcus faecalis, which exhibited clonal expansion of sequence type ST123. This ST123 clone accounted for 86 % of the DON group and was associated with an extensively drug-resistant (XDR) phenotype, showing resistance levels exceeding 128 μg/mL to last-resort antibiotics such as daptomycin, vancomycin, and linezolid. Additionally, DON upregulated the expression of critical daptomycin resistance genes (liaR, walK, liaS, mprF, and cls) in vancomycin-resistant enterococci (VRE) isolates. This study highlights the microbiological and environmental hazards that mycotoxins pose to the antibiotic resistance crisis.

2024-09-03·JAC-Antimicrobial Resistance

Dalbavancin-resistant Staphylococcus epidermidis in vivo selection following a prosthetic joint infection: phenotypic and genomic characterization

Article

作者: Corvec, S ; Fayoux, E ; Barbier, P ; Bémer, P ; Grégoire, M ; Nich, C ; Guillouzouic, A ; Ruffier d’Epenoux, L ; Lecomte, R ; Deschanvres, C

AbstractBackgroundDalbavancin is a lipoglycopeptide antibiotic with a wide spectrum of activity against Gram-positive bacteria, including MDR isolates. Its pharmacokinetic properties and administration patterns could be useful for the treatment of bone and joint infections, especially prosthetic joint infections (PJIs).IntroductionWe report the case of an 80-year-old man who experienced an acute periprosthetic joint infection of his right total knee arthroplasty (TKA). A DAIR procedure was done with tissue sampling, which allowed identification of a linezolid-resistant MDR S. epidermidis (LR-MDRSE) strain. The patient was then treated with dalbavancin (four injections).MethodsWe studied the phenotypic and genomic evolution of the strains and plasma through concentrations of dalbavancin at different points in time.ResultsAfter four injections (1500 mg IV) of dalbavancin over a 6 month period, the dalbavancin MIC increased 4-fold. Calculated fAUC0–24/MIC ratios were 945, 1239 and 766.5, respectively, at Days 49, 71 and 106, assuming an MIC of 0.032 mg/L. The PFGE dendrogram revealed 97% similarity among all the isolates. These results suggest acquisition by the S. epidermidis strain of dalbavancin resistance when the patient underwent dalbavancin treatment. A 4-amino-acid deletion in the walK gene coinciding with the emergence of phenotypic resistance was revealed by WGS without any other relevant indels.ConclusionsDespite dalbavancin treatment with pharmacokinetic management, emerging dalbavancin resistance in S. epidermidis was observed, resulting in treatment failure. This outcome led to a prosthesis revision and long-term suppressive antibiotic therapy, with no recurrence of PJI after an 18 month follow-up.

项与 WalK 相关的新闻（医药）

2024-11-19

·药咖荟

【CBIITA喜讯】创新中药专委会主委叶文才教授与合作团队发表抗耐药菌感染研究成果

叶文才 CBIITA创新中药专委会主委暨南大学副校长耐药菌感染特别是耐甲氧西林金黄色葡萄球菌 (MRSA) 感染，是威胁全球公共健康的重大问题。传统的抗生素已出现不同程度的耐药性问题，因此，开发新型抗生素迫在眉睫。氧杂蒽类天然产物具有显著的抗菌作用，但在天然中含量很低，限制了其进一步的开发利用，本文对这类化合物的化学合成和作用机制进行了研究。近日，暨南大学药学院叶文才教授/王磊研究员与第二临床医学院黄维研究员、南方科技大学李闯创教授、陆军军医大学邹全明教授合作，在 Nature Communications（IF=14.7）上发表了题为“Asymmetric total synthesis of polycyclicxanthenes anddiscovery of a WalK activator active against MRSA”的研究论文，首次完成了6个复杂天然多环氧杂蒽的集群式不对称全合成，并发现了首个具显著抗 MRSA 活性的新型 WalK 激活剂。作者开发了一条高效简洁的合成新策略，由廉价、商业可得的原料出发，利用新开发的光延反应介导的手性拆分，构建具有较大合成挑战性的中间体及其类似物。在此基础上，他们利用新开发的羟醛缩合-半缩酮/逆半缩酮-双迈克加成串联反应，差向选择性地构建了三个连续手性中心和6/6/6三环骨架，只需6步即可首次完成 myrtucommulones D-E、callistenone D、rhodomyrtosone R、myrtucomvalone D、callistenone C 的集群式不对称全合成，并确定了rhodomyrtosone R 和 callistenone C 的绝对构型以及通过理论计算解释了差向选择性构建了三个连续手性中心的机理（图1）。图1. 氧杂蒽类天然产物的化学结构完成了合成工作之后，该课题组对合成的66个化合物进行了系统性的抗菌活性实验，发现化合物(+)-22体外抗 MRSA 活性最强 (MIC 0.5 μg/mL)，其体内外抗 MRSA 活性与万古霉素相当。随后，他们对化合物 (+)-22的作用机制进行了研究（图2）。通过筛选自发耐药突变株结合全基因组测序技术，发现 WalK 蛋白可能是其作用靶点。进一步通过自溶活性、生物膜检测、表面等离子体共振（SPR）等实验，证实化合物(+)-22具有独特的通过激活 WalK 发挥抗菌作用的机制。图2. 化合物 (+)-22的抗菌作用机制综上所述，该论文首次采用光延反应介导的手性拆分和逆半缩酮-双迈克加成串联反应，高效构建6/6/6/三环骨架及4个手性中心，其中包括3个连续的手性中心。通过6步反应，首次实现了 myrtucommulones D-E 及其类似物的集群式不对称全合成。在此基础上，明确了活性化合物 (+)-22具有独特的通过激活 WalK 发挥抗菌活性的机制，其为第一个报道的具有显著抗菌活性的 WalK 激活剂。以上研究工作为研发新型抗 MRSA 耐药菌新药提供了科学依据。暨南大学副研究员程民井、博士研究生伍燕仪、陆军军医大学曾浩教授为共同第一作者。论文链接 https://doi.org/10.1038/s41467-024-49629-8 声明本微信公众号对所有原创、转载的内容、陈述、观点判断均保持中立，推送内容仅供公益性分享，部分转载作品、图片如有作者来源标记有误或涉及侵权，请联系小编删除。更多优质内容，欢迎关注↓ 媒体合作投稿转载/资料领取/加入社群请添加药小咖与/智/者/同/行为/创/新/赋/能

临床研究