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Journal of Biochemistry May 2024The rapid emergence of multi-drug-resistant bacteria has raised a serious public health concern. Therefore, new antibiotic developments have been highly desired. Here,...
The rapid emergence of multi-drug-resistant bacteria has raised a serious public health concern. Therefore, new antibiotic developments have been highly desired. Here, we propose a new method to visualize antibiotic actions on translating ribosomes in the cell-free system under macromolecular crowding conditions by cryo-electron microscopy, designated as the DARC method: the Direct visualization of Antibiotic binding on Ribosomes in the Cell-free translation system. This new method allows for acquiring a more comprehensive understanding of the mode of action of antibiotics on the translation inhibition without ribosome purification. Furthermore, with the direct link to biochemical analysis at the same condition as cryo-EM observation, we revealed the evolution of 2-DOS aminoglycosides from dibekacin (DBK) to arbekacin (ABK) by acquiring the synthetic tailored anchoring motif to lead to stronger binding affinity to ribosomes. Our cryo-EM structures of DBK and ABK bound ribosomes in the cell-free environment clearly depicted a synthetic tailored γ-amino-α-hydroxybutyryl (HABA) motif formed additional interactions with the ribosome enhancing antibiotic bindings. This new approach would be valuable for understanding the function of antibiotics for more efficient drug development.
Topics: Ribosomes; Cell-Free System; Aminoglycosides; Cryoelectron Microscopy; Anti-Bacterial Agents; Protein Biosynthesis
PubMed: 38227611
DOI: 10.1093/jb/mvae002 -
Journal of Pharmaceutical and... Nov 2022Ion-pair liquid chromatography with pulsed electrochemical detection (LC-PED) was established for the analysis of impurities in arbekacin (ABK) sulfate. APursuit...
Analysis of impurity profiling of arbekacin sulfate by ion-pair liquid chromatography coupled with pulsed electrochemical detection and online ion suppressor-ion trap-time off light mass spectrometry.
Ion-pair liquid chromatography with pulsed electrochemical detection (LC-PED) was established for the analysis of impurities in arbekacin (ABK) sulfate. APursuit pentafluorophenylpropyl (PFP) column was used as stationary phase. This novel method showed greater separation and sensitivity ability. In a representative ABK sample, 24 impurity peaks were detected in LC-PED, where of only 9 were monitored by a post-column derivatization method prescribed by the Japanese Pharmacopoeia (JP). For identification of the chemical structures of the impurities detected by LC-PED, LC-Mass Spectrometry (MS) was used. Two challenges had to be overcome in this work. The first was the transfer of the MS incompatible mobile phase to an MS compatibleone while maintaining the elution order of the peaks in the chromatograms. Previously reported approaches such as two-dimensional (2D)LC were hardly applicable in this case due to the lack of ultraviolet (UV) absorbing chromophores in ABK and its impurities. The sodium hydroxide solution was replaced by aqueous ammonia to adjust the pH of the mobile phase used in LC-PED. The other challenge encountered was the ion suppression effect caused by trifluoroacetic acid (TFA) and pentafluoroproponic acid (PFPA) in the mobile phase. Some strategies such as "TFA-fixed" and its modifications were tried, but they were inconvenient and severe contamination of the MS was observed. A cationself-regenerating suppressor (CSRS), which was originally designed for increasing analyte conductivityof ammonia and amines analysis in ion chromatography (IC), was coupled between the LC and Ion Trap-Time of Flight (IT-TOF)-MS and almost all TFA and PFPA in the mobile phase were removed. The limit of detection (LOD) of ABK in this integrated system improved significantly to 20 ng/mL. The chemical structures of the 28 impurities were elucidated and 15 impurities were reported for the first time.
Topics: Amines; Ammonia; Chromatography, High Pressure Liquid; Chromatography, Liquid; Dibekacin; Drug Contamination; Mass Spectrometry; Sodium Hydroxide; Sulfates; Trifluoroacetic Acid
PubMed: 36183632
DOI: 10.1016/j.jpba.2022.115061 -
Microbiology Spectrum Aug 2022Seven drug-resistant strains of Stenotrophomonas maltophilia were isolated from patients at two university hospitals in Nepal. S. maltophilia JUNP497 was found to encode...
Stenotrophomonas maltophilia from Nepal Producing Two Novel Antibiotic Inactivating Enzymes, a Class A β-Lactamase KBL-1 and an Aminoglycoside 6'--Acetyltransferase AAC(6')-Iap.
Seven drug-resistant strains of Stenotrophomonas maltophilia were isolated from patients at two university hospitals in Nepal. S. maltophilia JUNP497 was found to encode a novel class A β-lactamase, KBL-1 (Kathmandu β-lactamase), consisting of 286 amino acids with 52.98% identity to PSV-1. Escherichia coli transformants expressing were less susceptible to penicillins. The recombinant KBL-1 protein efficiently hydrolyzed penicillins. The genomic environment surrounding was a unique structure, with the upstream region derived from strains in China and the downstream region from strains in India. S. maltophilia JUNP350 was found to encode a novel 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap, consisting of 155 amino acids with 85.0% identity to AAC(6')-Iz. E. coli transformants expressing were less susceptible to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin and tobramycin. The recombinant AAC(6')-Iap protein acetylated all aminoglycosides tested, except for apramycin and paromomycin. The genomic environment surrounding was 90.99% identical to that of S. maltophilia JV3 obtained from a rhizosphere in Brazil. Phylogenetic analysis based on whole genome sequences showed that most S. maltophilia isolates in Nepal were similar to those isolates in European countries, including Germany and Spain. The emergence of drug-resistant S. maltophilia has become a serious problem in medical settings worldwide. The present study demonstrated that drug-resistant S. maltophilia strains in Nepal harbored novel genes encoding a class A β-lactamase, KBL-1, or a 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap. Genetic backgrounds of most S. maltophilia strains in Nepal were similar to those in European countries. Surveillance of drug-resistant S. maltophilia in medical settings in Nepal is necessary.
Topics: Acetyltransferases; Amino Acids; Anti-Bacterial Agents; Escherichia coli; Humans; Microbial Sensitivity Tests; Nepal; Penicillins; Phylogeny; Stenotrophomonas maltophilia; beta-Lactamases
PubMed: 35862995
DOI: 10.1128/spectrum.01143-22 -
Journal of Infection and Chemotherapy :... Sep 2022Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis...
INTRODUCTION
Reimbursements for pharmacist interventions and infectious disease teams have recently been introduced in Japan. Arbekacin (ABK) is used to treat pneumonia and sepsis caused by methicillin-resistant Staphylococcus aureus, and therapeutic drug monitoring (TDM) is recommended. This study aimed to clarify the trend in TDM implementation for ABK over time and the factors associated with TDM implementation using a claims database.
METHODS
Data of patients aged ≥15 years who received ABK for ≥3 consecutive days between 2010 and 2019 were extracted from a large Japanese medical claims database. The proportion of reimbursements claimed for TDM, pharmacist interventions, and the setup of infectious disease teams for each year were calculated. The factors associated with TDM implementation were identified using multivariate logistic regression analysis.
RESULTS
The proportion of TDM implementation for ABK increased by 9.1% from 2010 to 2019, but it remained less than 40% throughout this period. The proportion of TDM implementation was higher in patients who claimed reimbursements for pharmacist interventions than in patients who did not. Logistic regression analysis showed that the stationing of pharmacists in wards and long-term ABK treatment were significantly associated with TDM implementation.
CONCLUSIONS
From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial.
Topics: Aminoglycosides; Anti-Bacterial Agents; Dibekacin; Drug Monitoring; Humans; Japan; Methicillin-Resistant Staphylococcus aureus
PubMed: 35606308
DOI: 10.1016/j.jiac.2022.05.007 -
Nucleic Acids Research Jul 2021How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action...
How aminoglycoside antibiotics limit bacterial growth and viability is not clearly understood. Here we employ fast kinetics to reveal the molecular mechanism of action of a clinically used, new-generation, semisynthetic aminoglycoside Arbekacin (ABK), which is designed to avoid enzyme-mediated deactivation common to other aminoglycosides. Our results portray complete picture of ABK inhibition of bacterial translation with precise quantitative characterizations. We find that ABK inhibits different steps of translation in nanomolar to micromolar concentrations by imparting pleotropic effects. ABK binding stalls elongating ribosomes to a state, which is unfavorable for EF-G binding. This prolongs individual translocation step from ∼50 ms to at least 2 s; the mean time of translocation increases inversely with EF-G concentration. ABK also inhibits translation termination by obstructing RF1/RF2 binding to the ribosome. Furthermore, ABK decreases accuracy of mRNA decoding (UUC vs. CUC) by ∼80 000 fold, causing aberrant protein production. Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors.
Topics: Anti-Bacterial Agents; Dibekacin; Kinetics; Peptide Elongation Factor G; Peptide Termination Factors; Peptides; Protein Biosynthesis; Protein Synthesis Inhibitors; RNA, Messenger; RNA, Transfer, Amino Acyl; Ribosomes
PubMed: 34125898
DOI: 10.1093/nar/gkab495 -
Journal of Microbiology, Immunology,... Dec 2021Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
BACKGROUND
Arbekacin is a broad-spectrum aminoglycoside with activity against some Gram-positive and Gram-negative bacteria.
METHODS
Arbekacin minimum inhibitory concentration (MIC) values were determined for 296 drug-resistant Gram-negative bacilli, and compared to previously determined plazomicin, amikacin, gentamicin, and tobramycin MIC values.
RESULTS
The MIC values required to inhibit 50% and 90% of isolates (MIC and MIC, respectively) were 16 and >128 μg/ml, respectively.
CONCLUSIONS
Arbekacin showed similar MIC values to amikacin and gentamicin, a lower MIC value than tobramycin, and a higher MIC value than plazomicin.
Topics: Anti-Bacterial Agents; Dibekacin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests
PubMed: 32962921
DOI: 10.1016/j.jmii.2020.08.018 -
Journal of Infection and Chemotherapy :... Jan 2021Arbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Arbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis.
METHODS
A literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web.
RESULTS
Nine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15-16 μg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30-1.24). A trough arbekacin concentration of <2 μg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15-0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39-0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16-1.75).
CONCLUSIONS
Once-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 μg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15-16 μg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.
Topics: Anti-Bacterial Agents; Dibekacin; Drug Monitoring; Humans; Japan; Methicillin-Resistant Staphylococcus aureus
PubMed: 32828677
DOI: 10.1016/j.jiac.2020.08.002 -
Antimicrobial Agents and Chemotherapy Sep 2020ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial...
ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment and/or infection models, and surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log CFU reductions from baseline for , , and Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log CFU reduction from baseline at MIC values above the MIC value for (8 μg/ml), (4 μg/ml), and (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.
Topics: Anti-Bacterial Agents; Dibekacin; Humans; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus
PubMed: 32661000
DOI: 10.1128/AAC.02367-19 -
The Journal of the Association of... Jul 2019Antibiotic resistance is one of the biggest menace to global health. Deaths from Drug-resistant infections is set to escalate exponentially. Pipeline for new...
Antibiotic resistance is one of the biggest menace to global health. Deaths from Drug-resistant infections is set to escalate exponentially. Pipeline for new antibacterials is almost empty. The World Health Organization has reinforced its warning that to tackle growing threat of antimicrobial resistance, development of a new antibiotics is seriously lacking. Arbekacin is a novel aminoglycoside primarily used in the treatment of infections caused by resistant Staphylococcus Aureus i.e. Methicillin Resistant Staphylococcus Aureus (MRSA). Besides MRSA it also demonstrates activity against Enterococci and several Gram negative pathogens such as Klebsiella pneumonia, Pseudomonas aeruginosa, Acinetobacter baumannii including resistant strain. Arbekacin which has been used in Japan and Korea since more than two and half decades has been recently approved in India. This review will examine how Arbekacin evades the common mechanisms of antibiotic resistance, the pharmacokinetics of Arbekacin, and the various pharmacological properties and its spectrum of in vitro activity. The results of clinical trials on Arbekacin are also described, as is the patient safety and tolerability observed during these studies.
Topics: Anti-Bacterial Agents; Dibekacin; Drug Resistance, Bacterial; Humans; India; Japan; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections
PubMed: 31559785
DOI: No ID Found -
Therapeutic Drug Monitoring Feb 2020Arbekacin (ABK) is used to treat infections caused by methicillin-resistant Staphylococcus aureus and is used widely for the treatment of febrile neutropenia (FN). As...
BACKGROUND
Arbekacin (ABK) is used to treat infections caused by methicillin-resistant Staphylococcus aureus and is used widely for the treatment of febrile neutropenia (FN). As ABK has a narrow therapeutic concentration window, the dosage must be adjusted via therapeutic drug monitoring. However, the influence of the physiology of patients with FN on the pharmacokinetic (PK) parameters of ABK remains unclear. Therefore, we examined this influence on ABK PK parameters.
METHOD
We performed a retrospective cohort study using data from patients with a hematologic malignancy who were ≥18 years and had been administered ABK. We excluded patients who did not receive therapeutic drug monitoring and had an estimated glomerular filtration rate (eGFR) of <30 mL/min, because clinically sufficient data would not be available.
RESULT
Of the 99 enrolled patients, 25 did not have FN and 74 had FN. Arbekacin clearance (CLabk) was shown to correlate with eGFR in patients with FN (r = 0.32, P = 0.0062) and without FN (r = 0.50, P = 0.01). CLabk was higher in patients with FN than in those without FN. In addition, in the eGFR of <100 mL/min group (normal renal function), CLabk and CLabk/eGFR were also higher in patients with FN than in those without FN.
CONCLUSIONS
CLabk was increased in patients with FN and normal renal function; therefore, we propose an increased ABK dose for patients with FN and normal renal function.
Topics: Adult; Aged; Anti-Infective Agents; Cohort Studies; Dibekacin; Drug Monitoring; Febrile Neutropenia; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Retrospective Studies
PubMed: 31323015
DOI: 10.1097/FTD.0000000000000678