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Aminoglycosides

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Matthew E Falagas – One of the best experts on this subject based on the ideXlab platform.

  • Aminoglycoside therapy in infectious diseases
    Expert opinion on pharmacotherapy, 2013
    Co-Authors: Panagiotis Poulikakos, Matthew E Falagas
    Abstract:

    Introduction: Aminoglycosides are of the oldest antibiotics. Even though representatives of the class are used in various applications, the use that has established Aminoglycosides in medicine is their antimicrobial activity. Areas covered: Current knowledge on mechanism of action, adverse events, strategies to overcome toxicity and increase efficacy of Aminoglycosides, as well as therapeutic uses and future perspectives of this class of antibiotics. Expert opinion: Aminoglycosides are still the treatment of choice for diseases such as brucellosis and plague. Toxicity, along with the discovery of equally potent and less toxic antibiotics, has shelved Aminoglycosides the past 30 years. However, this has largely saved them from resistance development. Apart from retaining efficacy, strategies to overcome toxicity, especially once daily administration, has made Aminoglycosides a safer choice. Further, plazomicin is a very promising synthetic aminoglycoside that escapes all clinically significant aminoglycosi…

  • do we still need the Aminoglycosides
    International Journal of Antimicrobial Agents, 2009
    Co-Authors: Emanuele Durantemangoni, Matthew E Falagas, Alexandros P Grammatikos, Riccardo Utili
    Abstract:

    Since the introduction into clinical practice of the aminoglycoside class of antibiotics, a number of other antimicrobial agents with improved safety profile have entered the market. Studies have failed to demonstrate the superiority of aminoglycoside-containing regimens in a number of infection settings. This has raised doubts regarding the actual clinical utility of Aminoglycosides. However, the recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reconsider these ‘old’ antibacterial agents. This revived interest in the use of Aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity. Although some of the Aminoglycosides retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world, the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment make physicians reluctant to use these compounds in everyday practice. We believe that recent advances in the understanding of the effect of various dosage schedules of Aminoglycosides on toxicity combined with the retained (to a considerable degree) activity against the majority of Gram-negative bacterial isolates make this class of antibiotics still valuable in today’s clinical practice.

Stig Cronberg – One of the best experts on this subject based on the ideXlab platform.

  • Simplified monitoring of Aminoglycosides
    The Journal of antimicrobial chemotherapy, 1994
    Co-Authors: Stig Cronberg
    Abstract:

    For many years it has been standard practice to give Aminoglycosides in divided daily doses monitored by serum aminoglycoside assays. Recent experience indicates that Aminoglycosides can be given as a single daily dose with equal or better efficacy and equal or less toxicity. The single-daily dose regimen is both cheaper and more convenient. Recommended serum aminoglycoside concentrations immediately before the next dose, or 8 h later, vary according to whether a single daily dose or divided dose schedule is used. This is seldom realized in practice. Estimated creatinine clearance enables better prediction of the daily dose than was formerly recognized, and is to be preferred. Earlier fears of giving Aminoglycosides as a bolus intravenous injection have not been substantiated. After more than 40 years of use, we are beginning to learn how to monitor these potentially toxic drugs.

Gerard D. Wright – One of the best experts on this subject based on the ideXlab platform.

  • Aminoglycoside Resistance Mechanisms
    Frontiers in Antimicrobial Resistance, 2014
    Co-Authors: David D. Boehr, Ian F. Moore, Gerard D. Wright
    Abstract:

    The major target of Aminoglycosides is the bacterial ribosome, as first suggested by in vivo experiments demonstrating a marked decrease in protein synthesis following treatment of cells with Aminoglycosides and in vitro experiments on bacterial extracts showing that aminoglycoside treatment resulted in repression of both initiation and elongation in protein synthesis. Chemical footprinting studies and careful correlation analysis of ribosomal mutation with aminoglycoside resistance implicated specific ribosomal proteins and the tRNA binding site (A site) of the 16S rRNA as the most important determinants of aminoglycoside binding and action. There is some evidence that, at least in Escherichia coli, the oligopeptide binding protprotein, the periplasmic component of the major oligopeptide transport system, may play an important role in aminoglycoside uptake as mutants with reduced oligopeptide binding protprotein expression are resistant to Aminoglycosides. The most common aminoglycoside kinases are APH(3′)-IIIa and APH(2″)-Ia [C-terminal domain of the bifunctional aminoglycoside phosphotransferase-acetyltransferase AAC(6′)-APH(2″)] in gram-positive organisms, and APH(3′)-Ia and APH(3′)-IIa in gramnegative organisms. APH(3′)-I is the most common class of aminoglycoside kinase in gram-negative bacteria. ANT(2″)-Ia is one of the most important determinants of aminoglycoside resistance in gram-negative organisms. However, molecular research over the last decade has resulted in an excellent understanding of the mode of action, interaction with target, and various resistance mechanisms.

  • Bacterial resistance to aminoglycoside antibiotics
    Trends in microbiology, 1997
    Co-Authors: Julian Davies, Gerard D. Wright
    Abstract:

    The aminoglycoside antibiotics are broad-spectrum antibacterial compounds that are used extensively for the treatment of many bacterial infections. In view of the current concerns over the global rise in antibiotic-resistant microorganisms, there has been renewed interest in the mechanisms of resistance to the Aminoglycosides, including the superfamily of aminoglycoside-modifying enzymes.

  • kinetic mechanism of aminoglycoside phosphotransferase type iiia evidence for a theorell chance mechanism
    Journal of Biological Chemistry, 1995
    Co-Authors: Geoffrey A Mckay, Gerard D. Wright
    Abstract:

    Abstract Bacterial resistance to aminoglycoside-aminocyclitol antibiotics is mediated primarily by covalent modification of the drugs by a variety of enzymes. One such modifying enzyme, the 3′-aminoglycoside phosphotransferase, which is produced by Gram-positive cocci such as Enterococcus and Streptococcus inactivates a broad range of Aminoglycosides by ATP-dependent phosphorylation of specific hydroxyl residues on the antibiotics. Through the use of dead-end and product inhibitor studies, we present the first detailed examination of the kinetic mechanism for the 3′-aminoglycoside phosphotransferase-IIIa. Initial velocity patterns deduced from steady-state kinetics indicate a sequential mechanism with ordered binding of ATP first followed by aminoglycoside. Dead-end inhibition by AMP and adenylyl-imidodiphosphate is competitive versus ATP and noncompetitive versus kanamycin A. Dead-end inhibition by tobramycin, a kanamycin analogue lacking a 3′-OH, is competitive versus both kanamycin A and uncompetitive versus ATP, indicative of ordered substrate binding where ATP must add prior to aminoglycoside addition. Product inhibition by kanamycin phosphate is noncompetitive versus ATP when kanamycin A is held at subsaturating concentrations (Km), whereas no inhibition is observed when the concentration of kanamycin A is held at 10 Km. This is consistent with kanamycin phosphate being the first product released followed by ADP release. The patterns of inhibition observed support a mechanism where ATP binding precedes aminoglycoside binding followed by a rapid catalytic step. Product release proceeds in an ordered fashion where kanamycin phosphate is released quickly followed by a slow release of ADP. Aminoglycoside substrates, such as kanamycin A, show substrate inhibition that is uncompetitive versus ATP. This indicates binding of the Aminoglycosides to the slowly dissociating (E•ADP) complex at high drug concentrations. These experiments are consistent with a Theorell-Chance kinetic mechanism for 3′-aminoglycoside phosphotransferase-IIIa.

C L Terrell – One of the best experts on this subject based on the ideXlab platform.

  • The Aminoglycosides.
    Mayo Clinic proceedings, 1991
    Co-Authors: R S Edson, C L Terrell
    Abstract:

    Despite the introduction of newer, less toxic antimicrobial agents, the Aminoglycosides continue to serve a useful role in the treatment of serious enterococcal and gram-negative bacillary infections. Gentamicin, because of its low cost, remains the aminoglycoside of choice in hospitals with low levels of resistance among Enterobacteriaceae and Pseudomonas aeruginosa. Amikacin is useful against gentamicin-resistant gram-negative bacilli and also in the treatment of infections caused by susceptible Nocardia and nontuberculous mycobacteria. An alarming increase in resistance to Aminoglycosides among enterococci has been noted, despite little change in susceptibility patterns among gram-negative bacilli. Future efforts will need to be directed toward a better understanding of mechanisms of antimicrobial resistance and toward the prevention of aminoglycoside-induced toxicity.

Sylvie Garneautsodikova – One of the best experts on this subject based on the ideXlab platform.

  • exploring the substrate promiscuity of drug modifying enzymes for the chemoenzymatic generation of n acylated Aminoglycosides
    ChemBioChem, 2009
    Co-Authors: Keith D Green, Sylvie Garneautsodikova, Wei Chen, Jacob L Houghton, Micha Fridman
    Abstract:

    Aminoglycosides are broad-spectrum antibiotics commonly used for the treatment of serious bacterial infections. Decades of clinical use have led to the widespread emergence of bacte- rial resistance to this family of drugs limiting their efficacy in the clinic. Here, we report the development of a methodology that utilizes aminoglycoside acetyltransferases (AACs) and un- natural acyl coenzyme A analogues for the chemoenzymatic generation of N-acylated aminoglycoside analogues. Genera- tion of N-acylated Aminoglycosides is followed by a simple qualitative test to assess their potency as potential antibacteri- als. The studied AACs (AAC(6′)-APH(2”) and AAC(3)-IV) show di- verse substrate promiscuity towards a variety of aminoglyco- sides as well as acyl coenzyme A derivatives. The enzymes were also used for the sequential generation of homo- and hetero-di-N-acylated Aminoglycosides. Following the clinical success of the N-acylated amikacin and arbekacin, our chemo- enzymatic approach offers access to regioselectively N-acylated Aminoglycosides in quantities that allow testing of the antibac- terial potential of the synthetic analogues making it possible to decide which molecules will be worth synthesizing on a larger scale.