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Last update 08 May 2025

WalK

Last update 08 May 2025

Basic Info

Synonyms

Sensor histidine kinase WalK

Introduction

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).

Drugs associated with WalK

Signermycin B

Target

WalK

Mechanism

Walk protein inhibitors

Active Org.

Kinki University

Originator Org.

Kinki University

Active Indication

Gram-Positive Bacterial Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

WalK activator(Jinan University)

Target

WalK

Mechanism

Walk protein activators

Active Org.

Jinan University

Originator Org.

Jinan University

Active Indication

MRSA - Methicillin resistant Staphylococcus aureus infection

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Walkmycin C

Target

WalK

Mechanism

Walk protein inhibitors

Active Org.-

Originator Org.

Kinki University

Active Indication-

Inactive Indication

Proteobacteria infection

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with WalK

100 Translational Medicine associated with WalK

0 Patents (Medical) associated with WalK

110

Literatures (Medical) associated with WalK

02 Apr 2025·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

Author: 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.

01 Mar 2025·Environment International

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

Article

Author: 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.

03 Sep 2024·JAC-Antimicrobial Resistance

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

Article

Author: 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.

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