Regio‐ and Chemoselective 6′‐N‐Derivatization of Aminoglycosides: Bisubstrate Inhibitors as Probes To Study Aminoglycoside 6′‐<i>N</i>‐Acetyltransferases

Gao, Feng; Yan, Xuxu; Baettig, Oliver M.; Berghuis, A.M.; Auclair, Karine

doi:10.1002/ange.200501399

Cited by 26 publications

(52 citation statements)

References 32 publications

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“…242 These bisubstrate analogues mimic the proposed tetrahedral intermediate, resulting in structures with amide-based aminoglycoside-CoA linkages. The compounds detailed in Reference 242 provide insight into the reactions of acetyltransferases based on knowledge of their structures, however, more detailed kinetic and thermodynamic investigations are required to determine the effect of these inhibitors on the cooperative mechanism.…”

Section: Aminoglycoside N-(6’)-acetyltransferase IImentioning

confidence: 93%

“…239,242 The 2003 report of Draker et al describes partial competitive inhibition of AAC(6’)-Ii by desulfo-CoA, expressed as K is = α K i , where α is the change in K m when the inhibitor is bound to the ES complex. At varied concentrations of AcCoA, K is is reported to be 6.58 ± 2.18 μM.…”

Section: Aminoglycoside N-(6’)-acetyltransferase IImentioning

confidence: 99%

“…242 with ( A ) varying substituent groups appended to the ring system and ( B ) varying linker length between the amide-CoA thioester bond. Nanomolar (nM) inhibition constants (K i ) for the compounds 1-3 in ( A ) are (1) 76 ± 25; (2) 111 ± 28; (3) 119 ± 14.…”

Section: Figurementioning

confidence: 99%

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Solution NMR Spectroscopy for the Study of Enzyme Allostery

2016

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Allostery is a ubiquitous biological regulatory process in which distant binding sites within a protein or enzyme are functionally and thermodynamically coupled. Allosteric interactions play essential roles in many enzymological mechanisms, often facilitating formation of enzyme-substrate complexes and/or product release. Thus, elucidating the forces that drive allostery is critical to understanding the complex transformations of biomolecules. Currently, a number of models exist to describe allosteric behavior, taking into account energetics as well as conformational rearrangements and fluctuations. In the following review, we discuss the use of solution NMR techniques designed to probe allosteric mechanisms in enzymes. NMR spectroscopy is unequaled in its ability to detect structural and dynamical changes in biomolecules, and the case studies presented herein demonstrate the range of insights to be gained from this valuable method. We also provide a detailed technical discussion of several specialized NMR experiments that are ideally suited for the study of enzymatic allostery.

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Section: Aminoglycoside N-(6’)-acetyltransferase IImentioning

confidence: 93%

Section: Aminoglycoside N-(6’)-acetyltransferase IImentioning

confidence: 99%

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Solution NMR Spectroscopy for the Study of Enzyme Allostery

2016

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“…Further research led to synthesis of other bisubstrates of smaller size by using truncated aminoglycosides or CoA. One of the compounds, showed a synergistic effect with kanamycin on the growth of E. faecium harboring AAC(6′)-Ii, an enzyme that catalyzes acetylation through an ordered mechanism (Draker et al, 2003; Gao et al, 2005; Gao et al, 2006). Subsequent kinetic and structural studies using AAC(6′)-Iy, which binds the substrates on a random manner, as a target found that the bisubstrates analyzed bind to this enzyme with much lower affinity (Magalhaes et al, 2008).…”

Section: Strategies To Overcome the Effect Of Aminoglycoside Modifmentioning

confidence: 99%

Aminoglycoside modifying enzymes

Ramírez

Tolmasky

2010

Drug Resistance Updates

1,122

1,060

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Aminoglycosides have been an essential component of the armamentarium in the treatment of lifethreatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymatic modification is the most prevalent in the clinical setting. Aminoglycoside modifying enzymes catalyze the modification at different −OH or −NH 2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The number of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymatic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymatic action or of the expression of the modifying enzymes. Keywordsantibiotic resistance; aminoglycoside; aminoglycoside modifying enzyme; acetyltransferase; nucleotidyltransferase; phosphotransferase; kinase; antisense; RNase P; RNase H; bacterial infection 1. A brief overview of aminoglycoside antibiotics General aspectsAminoglycoside antibiotics are a complex family of compounds characterized for having an aminocyclitol nucleus (streptamine, 2-deoxystreptamine, or streptidine) linked to amino sugars through glycosidic bonds. In addition, other compounds such as spectinomycin, which is an aminocyclitol not linked to amino sugars, or compounds that include the aminocyclitol fortamine are also included in this family (Bryskier, 2005;Veyssier and Bryskier, 2005). Aminoglycosides are primarily used in the treatment of infections caused by gram-negative aerobic bacilli, staphylococci, and other gram-positives (Yao and

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“…[10][11][12][13][14][15][16][17] During the past two decades, significant efforts have been devoted to the design of new aminoglycoside antibiotics that are immune to inactivation [18] and also to the preparation of specific enzymatic inhibitors that could be co-administered in tandem with natural antibiotics. [19] Unfortunately, few examples of successful designs have been reported and none of them has entered clinical use, thus reflecting our limited understanding of the basic thermodynamic, kinetic and mechanistic features of the drug inactivation process. Evidently, medicinal chemistry efforts would greatly benefit from an insightful knowledge of the basic properties of aminoglycoside-modifying enzymes.…”

Section: Introductionmentioning

confidence: 99%

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

Matesanz

Dı́az

Corzana

et al. 2012

Chemistry A European J

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The most common mode of bacterial resistance to aminoglycoside antibiotics is the enzyme-catalysed chemical modification of the drug. Over the last two decades, significant efforts in medicinal chemistry have been focused on the design of non- inactivable antibiotics. Unfortunately, this strategy has met with limited success on account of the remarkably wide substrate specificity of aminoglycoside-modifying enzymes. To understand the mechanisms behind substrate promiscuity, we have performed a comprehensive experimental and theoretical analysis of the molecular-recognition processes that lead to antibiotic inactivation by Staphylococcus aureus nucleotidyltransferase 4'(ANT(4')), a clinically relevant protein. According to our results, the ability of this enzyme to inactivate structurally diverse polycationic molecules relies on three specific features of the catalytic region. First, the dominant role of electrostatics in aminoglycoside recognition, in combination with the significant extension of the enzyme anionic regions, confers to the protein/antibiotic complex a highly dynamic character. The motion deduced for the bound antibiotic seem to be essential for the enzyme action and probably provide a mechanism to explore alternative drug inactivation modes. Second, the nucleotide recognition is exclusively mediated by the inorganic fragment. In fact, even inorganic triphosphate can be employed as a substrate. Third, ANT(4') seems to be equipped with a duplicated basic catalyst that is able to promote drug inactivation through different reactive geometries. This particular combination of features explains the enzyme versatility and renders the design of non-inactivable derivatives a challenging task.

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Regio‐ and Chemoselective 6′‐N‐Derivatization of Aminoglycosides: Bisubstrate Inhibitors as Probes To Study Aminoglycoside 6′‐N‐Acetyltransferases

Cited by 26 publications

References 32 publications

Solution NMR Spectroscopy for the Study of Enzyme Allostery

Solution NMR Spectroscopy for the Study of Enzyme Allostery

Aminoglycoside modifying enzymes

Multiple Keys for a Single Lock: The Unusual Structural Plasticity of the Nucleotidyltransferase (4′)/Kanamycin Complex

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