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PubMed2002

Sequence-specific recognition of the major groove of RNA by deoxystreptamine.

Aminoglycoside antibiotics specifically interact with a variety of RNA sequences, and in particular with the decoding region of 16S ribosomal RNA in the aminoacyl tRNA acceptor site (A-site). Ring II of aminoglycosides (2-deoxystreptamine) is the most conserved element among aminoglycoside antibiotics that bind to the A-site. NMR structures of aminoglycoside-A-site RNA complexes suggested that the 2-deoxystreptamine core of aminoglycosides specifically recognizes (5')G-U(3') and potentially (5')G-G(3') or (5')U-G(3') steps in the major groove of RNA. Here, we show that isolated deoxystreptamine specifically interacts with G-U steps within the major groove of the A-site RNA. The bulge residue of A-site RNA is required to open the major groove for accommodation of deoxystreptamine. The chemical groups of deoxystreptamine presented to the RNA by the framework of the 6-carbon ring modulate RNA recognition.

Anti-Bacterial Agents↗
PubMed2002

Thermodynamics of aminoglycoside and acyl-coenzyme A binding to the Salmonella enterica AAC(6')-Iy aminoglycoside N-acetyltransferase.

Kinetic and mechanistic studies on the chromosomally encoded aminoglycoside 6'-N-acetyltransferase, AAC(6')-Iy, of Salmonella enterica that confers resistance toward aminoglycosides have been previously reported [Magnet et al. (2001) Biochemistry 40, 3700-3709]. In the present study, equilibrium binding and the thermodynamic parameters of binding of aminoglycosides and acyl-coenzyme A derivatives to AAC(6')-Iy and of two mutants, C109A and the C109A/C70A double mutant, have been studied using fluorescence spectroscopy and isothermal titration calorimetry (ITC). Association constants for different aminoglycosides varied greatly (4 x 10(4)-150 x 10(4)) while the association constants of several acyl-coenzyme A derivatives were similar (3.2 x 10(4)-4.5 x 10(4)). The association constants and van't Hoff enthalpy changes derived from intrinsic protein fluorescence changes were in agreement with independently measured values from isothermal titration calorimetry studies. Binding of both aminoglycosides and acyl-coenzyme A derivatives is strongly enthalpically driven and revealed opposing negative entropy changes, resulting in enthalpy-entropy compensation. The acetyltransferase exhibited a temperature-dependent binding of tobramycin with a negative heat capacity value of 410 cal mol(-1) K(-1). Isothermal titration studies of acetyl-coenzyme A and tobramycin binding to mutant forms of the enzyme indicated that completely conserved C109 does not play any direct role in the binding of either of the substrates, while C70 is directly involved in aminoglycoside binding. These results are discussed and compared with previous steady-state kinetic studies of the enzyme.

Acetyltransferases↗
PubMed2002

Stereospecificity of aminoglycoside-ribosomal interactions.

Aminoglycoside antibiotics bind to the A-site decoding region of bacterial rRNA causing mistranslation and/or premature message termination. Aminoglycoside binding to A-site RNA decoding region constructs is established here to be only weakly stereospecific. Mirror-image prokaryotic A-site decoding region constructs were prepared in the natural D-series and the enantiomeric L-series and tested for binding to a series of aminoglycosides. In general, aminoglycosides bind to the D-series decoding region constructs with 2-3-fold higher affinities than they bind to the enantiomeric L-series. Moreover, L-neamine, the enantiomer of naturally occurring D-neamine, was prepared and shown to bind approximately 2-fold more weakly than D-neamine to the natural series decoding region construct, a result consistent with weakly stereospecific binding. The binding of naturally occurring D-neamine and its synthetic L-enantiomer was further evaluated with respect to binding to prokaryotic and eukaryotic ribosomes. Here, weak stereospecifcity was again observed with L-neamine being the more potent binder by a factor of approximately 2. However, on a functional level, unnatural L-neamine proved to inhibit in vitro translation with significantly lower potency (approximately 5-fold) than D-neamine. In addition, both L- and D-neamine are bacteriocidal toward Gram-(-) bacteria. L-Neamine inhibits the growth of E. coli and P. aeruginosa with 8- and 3-fold higher MIC than D-neamine. Interestingly, L-neamine also inhibits the growth of aminoglycoside-resistant E. coli, which expresses a kinase able to phosphorylate and detoxify aminoglycosides of the D-series. These observations suggest that mirror-image aminoglycosides may avoid certain forms of enzyme-mediated resistance.

Anti-Bacterial Agents↗
PubMed1997

Structure-based discovery of ligands targeted to the RNA double helix.

Ligands capable of specific recognition of RNA structures are of interest in terms of the principles of molecular recognition as well as potential chemotherapeutic applications. We have approached the problem of identifying small molecules with binding specificity for the RNA double helix through application of the DOCK program [Kuntz, I. D., Meng, E. C., and Shoichet, B. K. (1994) Acc. Chem. Res. 27, 117-123], a structure-based method for drug discovery. A series of lead compounds was generated through a database search for ligands with shape complementarity to the RNA deep major groove. Compounds were then evaluated with regard to their fit into the minor groove of B DNA. Those compounds predicted to have an optimal fit to the RNA groove and strong discrimination against DNA were examined experimentally. Of the 11 compounds tested, 3, all aminoglycosides, exhibited pronounced stabilization of RNA duplexes against thermal denaturation with only marginal effects on DNA duplexes. One compound, lividomycin, was examined further, and shown to facilitate the ethanol-induced B to A transition in calf thymus DNA. Fluorine NMR solvent isotope shift measurements on RNA duplexes containing 5-fluorouracil provided evidence that lividomycin binds in the RNA major groove. Taken together, these results indicate that lividomycin recognizes the general features of the A conformation of nucleic acids through deep groove binding, confirming the predictions of our DOCK analysis. This approach may be of general utility for identifying ligands possessing specificity for additional RNA structures as well as other nucleic acid structural motifs.

Aminoglycosides↗
PubMed1999

Specificity in the binding of aminoglycosides to HIV-RRE RNA.

Quantitative studies of the binding of neomycin B to RRE constructs are carried out to determine the relationship between non-Watson Crick base-paired elements in the RNA and aminoglycoside binding. The RRE region contains two unpaired domains containing a single base bulge and a bubble structure, respectively. Deletion of the single base bulge has no effect on neomycin binding as the site of aminoglycoside binding is localized to the bubble region. Converting the bubble region into an A-form duplex gradually abolishes neomycin B binding in 3-5-fold steps in affinity over a 75-fold range. Thus, the binding of aminoglycoside is favored at domains in RNA that are nonduplex in nature, but aminoglycoside binding is only graded-specific in that affinities are enhanced gradually as the structure further deviates from a duplex form. It is likely that high-affinity aminoglycoside binding does not occur in duplex RNA because the major groove is too narrow to allow for aminoglycoside access and that structural perturbations that allow widening of the groove facilitate access. However, these interactions are only graded-specific with respect to both aminoglycoside structure and RNA domain structure.

Anti-Bacterial Agents↗
PubMed2003

The complex of a designer antibiotic with a model aminoacyl site of the 30S ribosomal subunit revealed by X-ray crystallography.

The ribosome is an important target for aminoglycoside antibiotics; however, the clinical effectiveness of aminoglycosides has diminished due to bacterial resistance mechanisms. Here we report the X-ray structure of a novel synthetic aminoglycoside bound to the A site of the ribosome, its target for manifestation of activity. The structure validates the in silico design paradigms for the antibiotic and reveals the molecular interactions made by this novel antibiotic in prokaryotes.

Anti-Bacterial Agents↗
PubMed2006

Aminoglycoside-induced reduction in nucleotide mobility at the ribosomal RNA A-site as a potentially key determinant of antibacterial activity.

Steady-state and time-resolved fluorescence techniques have been used to characterize the energetics and dynamics associated with the interaction of an E. coli 16 S rRNA A-site model oligonucleotide and four aminoglycoside antibiotics that exhibit a broad range of antibacterial activity. The results of these characterizations suggest that aminoglycoside-induced reduction in the mobility of an adenine residue at position 1492 of the rRNA A-site is a more important determinant of antibacterial activity than drug affinity for the A-site. This observation is consistent with a recently proposed model for the mechanism of protein synthesis inhibition by aminoglycosides that invokes a drug-induced alteration in the conformational equilibrium of the rRNA A-site (centered around the conserved adenine residues at positions 1492 and 1493), which, in turn, promotes an enhanced interaction between the rRNA and the minihelix formed by the tRNA anticodon and the mRNA codon, even when the anticodon is noncognate. Regarded as a whole, the results reported here indicate that the rational design of antibiotics that target the 16 S rRNA A-site requires consideration of not only the structure and energetics of the drug-RNA complex but also the dynamics associated with that complex.

2-Aminopurine↗
PubMed1997

Direct observation of aminoglycoside-RNA interactions by surface plasmon resonance.

The specificity of neomycin B and related aminoglycoside antibiotics in their interaction with the Rev responsive element (RRE) of HIV-1 mRNA has been studied by directly observing the aminoglycoside-RNA complexes using surface plasmon resonance. Several different RNA sequences, each with a biotin tag, have been prepared using T7 RNA polymerase-catalyzed transcription of synthetic DNA templates and have been immobilized on a streptavidin-coated surface for the binding study. The results indicate that neomycin B is not specific for the G-rich bubble region in RRE. Rather, it appears to interact with three different sites, each with a submicromolar dissociation constant, within the 67-nucleotide domain II of RRE. Further analysis of neomycin B binding with three short synthetic RNA hairpins showed binding with submicromolar affinity and 1:1 stoichiometry in each case. This suggests that neomycin B may generally bind with this affinity to regular A-form RNA or hairpin loops. The approach described here is generally useful for understanding the fundamental interactions involved in the specific recognition of nucleic acids by small molecules which is the basis of rational drug design.

Anti-Bacterial Agents↗
PubMed2003

[Liver abscess: a practical approach].

The management of a liver abscess suspected on the basis of clinical and radiological findings is radically different depending on its amoebic or pyogenic etiology. Medical management is usually enough to treat amoebic abscess, the prognosis of which is excellent while percutaneous aspiration puncture, drainage and antibiotics is the rule in pyogenic abscess, the prognosis of which depends on the quickness of diagnosis and risk factors associated. This article first relates a case of liver abscess we had in our service and then propose, on the basis of a literature review, a synthesis of the different characteristics, diagnostic and therapeutic approaches and follow-up of amoebic and pyogenic liver abscesses.

Adult↗
PubMed2000

Conformational switch in the decoding region of 16S rRNA during aminoacyl-tRNA selection on the ribosome.

Binding of aminoglycoside antibiotics to 16S ribosomal RNA induces a particular structure of the decoding center and increases the misincorporation of near-cognate amino acids. By kinetic analysis we show that this is due to stabilization of the near-cognate codon recognition complex and the acceleration of two rearrangements that limit the rate of amino acid incorporation. The same rearrangement steps are accelerated in the cognate coding situation. We suggest that cognate codon recognition, or near-cognate codon recognition augmented by aminoglycoside binding, promote the transition of 16S rRNA from a 'binding' to a 'productive' conformation that determines the fidelity of decoding.

Anti-Bacterial Agents↗
PubMed2004

Leishmaniasis.

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Animals↗
PubMed2001

Drug resistance in Indian visceral leishmaniasis.

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.

Aminoquinolines↗