Arbekacin: another novel agent for treating infections due to methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens

Matsumoto, Tetsuya

doi:10.2147/cpaa.s44377

Cited by 23 publications

(22 citation statements)

References 42 publications

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“…16 ABK is a semisynthetic AG that has regained popularity over the past few decades. When an ( S )-4-amino-2-hydroxybutyryl (AHB) group was appended to its precursor dibekacin, ABK was shown to possess antimicrobial activity better than that of AMK and GEN and to be less prone to the development of bacterial resistance than other AHB-lacking AGs.…”

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confidence: 99%

Expanding Aminoglycoside Resistance Enzyme Regiospecificity by Mutation and Truncation

Holbrook

2016

Biochemistry

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Aminoglycosides (AGs) are broad-spectrum antibiotics famous for their antibacterial activity against Gram-positive and Gram-negative bacteria, as well as mycobacteria. In the United States, the most prescribed AGs, including amikacin (AMK), gentamicin (GEN), and tobramycin (TOB), are vital components of the treatment for resistant bacterial infections. Arbekacin (ABK), a semisynthetic AG, is widely used for the treatment of resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus in Asia. However, the rapid emergence and development of bacterial resistance are limiting the clinical application of AG antibiotics. Of all bacterial resistance mechanisms against AGs, the acquisition of AG-modifying enzymes (AMEs) by bacteria is the most common. It was previously reported that a variant of a bifunctional AME, the 6′-N-AG acetyltransferase-Ie/2″-O-AG phosphotransferase-Ia [AAC(6′)-Ie/APH(2″)-Ia], containing a D80G point mutation and a truncation after amino acid 240 modified ABK and AMK at a new position, the 4′″-amine, therefore displaying a change in regiospecificity. In this study, we aimed to verify the altered regiospecificity of this bifunctional enzyme by mutation and truncation for the potential of derivatizing AGs with chemoenzymatic reactions. With the three variant enzymes in this study that contained either mutation only (D80G), truncation only (1–240), or mutation and truncation (D80G-1–240), we characterized their activity by profiling their substrate promiscuity, determined their kinetics parameters, and performed mass spectrometry to determine how and where ABK and AMK were acetylated by these enzymes. We found that the three mutant enzymes possessed distinct acetylation regiospecificity compared to that of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme and the functional AAC(6′)-Ie domain [AAC(6′)/APH(2″)-1–194].

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Expanding Aminoglycoside Resistance Enzyme Regiospecificity by Mutation and Truncation

Holbrook

2016

Biochemistry

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“…Recently, the U.S. Food and Drug Administration approved arbekacin for use under a protocol at the Walter Reed National Military Medical Center to treat infections for which no other antibiotic is available. Importantly, arbekacin is refractory to nearly all AMEs with the exception of some members of the AAC(6=)-I family and the bifunctional enzyme AAC(6=)/APH(2==) produced by some strains of S. aureus and enterococci (3,4,(6)(7)(8). However, even though these enzymes acetylate arbekacin, the antibiotic still retains some antimicrobial activity (9).…”

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confidence: 99%

“…Arbekacin is a semisynthetic aminoglycoside derived from dibekacin (4). It is licensed only in Japan, where it is used to treat septicemia and pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA).…”

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Detecting 16S rRNA Methyltransferases in Enterobacteriaceae by Use of Arbekacin

et al. 2016

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c 16S rRNA methyltransferases confer resistance to most aminoglycosides, but discriminating their activity from that of aminoglycoside-modifying enzymes (AMEs) is challenging using phenotypic methods. We demonstrate that arbekacin, an aminoglycoside refractory to most AMEs, can rapidly detect 16S methyltransferase activity in Enterobacteriaceae with high specificity using the standard disk susceptibility test. Aminoglycosides play an important role in treating serious infections caused by Gram-positive and -negative organisms, with amikacin, gentamicin, and tobramycin being of particular clinical value (1). In Gram-negative organisms, resistance is primarily mediated by aminoglycoside-modifying enzymes (AMEs), which inactivate the antibiotic through modification of the -OH or -NH 2 groups (2). AMEs are divided into three classes: the ATP (and/or GDP)-dependent aminoglycoside phosphotransferases (APHs), the acetyl-coenzyme A (CoA)-dependent aminoglycoside acetyltransferases (AACs), and the ATP-dependent aminoglycoside nucleotidyltransferases (ANTs) (2). Different classes have different antibiotic substrates, but no single AME confers resistance to all aminoglycosides. In the past decade, transmissible 16S rRNA methyltransferases (16S RMTases) have emerged as a new and worrisome source of aminoglycoside resistance that operates by reducing the affinity of nearly all aminoglycosides for 16S rRNA via ribosomal methylation (3). Since the presence of multiple AMEs can confer resistance to all clinically relevant aminoglycosides, discriminating between AME RMTase activity and 16S RMTase activity using phenotypic methods can be challenging (3).Arbekacin is a semisynthetic aminoglycoside derived from dibekacin (4). It is licensed only in Japan, where it is used to treat septicemia and pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). However, it also has broad antibacterial activity against Gram-negative bacteria, including strains that are resistant to amikacin, gentamicin, and tobramycin (5). Recently, the U.S. Food and Drug Administration approved arbekacin for use under a protocol at the Walter Reed National Military Medical Center to treat infections for which no other antibiotic is available. Importantly, arbekacin is refractory to nearly all AMEs with the exception of some members of the AAC(6=)-I family and the bifunctional enzyme AAC(6=)/APH(2==) produced by some strains of S. aureus and enterococci (3,4,(6)(7)(8). However, even though these enzymes acetylate arbekacin, the antibiotic still retains some antimicrobial activity (9). We exploited this characteristic to develop a rapid method to detect 16S RMTase activity in Enterobacteriaceae using arbekacin-impregnated susceptibility disks.125 Escherichia coli, 74 Klebsiella pneumoniae, and 22 other Enterobacteriaceae isolates, including Enterobacter (n ϭ 4), Morganella (n ϭ 2), Proteus (n ϭ 3), Providencia (n ϭ 6), Serratia (n ϭ

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“…Arbekacin causes membrane damage and binds both to the 50s and 30S ribosomal subunits, resulting in codon misreading and inhibition of translation [13]. Arbekacin is not inactivated by aminoglycoside-inactivating enzymes [14]. Arbekacin shows the most potent antibacterial effect against clinically isolated MRSA strains among the aminoglycosides such as gentamicin, tobramycin, and amikacin [15], and the antibacterial effect of arbekacin is equivalent to that of vancomycin [15].…”

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confidence: 99%

Clinical Characteristics of Invasive Methicillin-Resistant Staphylococcus aureus at General Hospital in the Central Region of Japan from July 2014 to June 2015

Minami¹,

Sakakibara²,

Imura³

et al. 2015

JBM

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Methicillin-resistant Staphylococcus aureus is crucial pathogen caused severe invasive infection disease. This study was conducted to find out the prevalence and antimicrobial susceptibility pattern of invasive Methicillin-resistant Staphylococcus aureus isolates at general hospital in the central region of Japan from July 2014 to June 2015. Methicillin-resistant Staphylococcus aureus was identified by standard laboratory procedure. Antimicrobial susceptibility testing was performed by micro dilution assay according to CLSI recommendation. Invasive Methicillin-resistant Staphylococcus aureus disease was defined as isolation of bacteria from a normally sterile body site. One hundred seventy-one methicillin-resistant Staphylococcus aureus were isolated among which 95 (55.6%) were from inpatient and 76 (44.4%) were from outpatient. The age incidence of (0 -1) years, (1 -10) years, (11 -40) years, (41 -60) years and >60 years age groups were 18 (10.5%), 41 (24.0%), 15 (8.8%), 5 (2.9%), and 92 (53.8%) respectively. There was significant difference of age distribution between invasive and noninvasive disease in 0 -1 years group and 11 -40 years age group. Positive samples were received mostly from the pediatrics (56/32.7%), respiratory medicine (25/14.6%) and general medicine (25/14.6%). We also found the significant differences of department between invasive and noninvasive disease in pediatrics, dermatology, and surgery. Arbekacin, teicoplanin, and vancomycin were the most active antibiotics with 100% susceptible rates in our study. Our study revealed that erythromycin and gentamicin were more antimicrobial effective in invasive disease than in noninvasive disease significantly. Methicillin-resistant Staphylococcus aureus infection spreads worldwide easily and inadequate use of antibiotics contributes to uptake of their new antimicrobial resistance. Continuous antimicrobial surveys are need for guiding policy on the adequate use of antibiotics to reduce the morbidity and mortality.

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Arbekacin: another novel agent for treating infections due to methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens

Cited by 23 publications

References 42 publications

Expanding Aminoglycoside Resistance Enzyme Regiospecificity by Mutation and Truncation

Expanding Aminoglycoside Resistance Enzyme Regiospecificity by Mutation and Truncation

Detecting 16S rRNA Methyltransferases in Enterobacteriaceae by Use of Arbekacin

Clinical Characteristics of Invasive Methicillin-Resistant Staphylococcus aureus at General Hospital in the Central Region of Japan from July 2014 to June 2015

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