Aminoglycoside complexes with

Since aminoglycoside complexes with membrane phosphoinositides are extremely stable, they could well exist in an intracellular environment with concentrations of aminoglycosides that are achieved in chemotherapeutic treatment. 

In order to analyze the effect that conformational restriction has on the antibiotic enzymatic inactivation, three different enzymes were chosen as model systems Staphylococcus aureus ANT(4 ), Mycobacterium tuberculosis AAC(2 ) and Enterococcus faecalis APH(3 ). These proteins are representative of the three main families of enzymes that modify aminoglycosides adenyltrans-ferases, acyltransferases and phosphotransferases. In addition, there is high resolution X-ray structural information available for the three enzymes in complex with several antibiotics. 

S. C., Puglisi, J. D. Structure of the A site of Escherichia coli 16 S ribosomal RNA complexed with an aminoglycoside antibiotic. Science 1996,... 

The NMR structures of aminoglycosides in complex with the A-site oligo also elucidate the structural origins of antibiotic-induced miscoding. To ensure... 

The structures of tobramycin and neomycin B in complex with aptamer RNAs also display the importance of interactions between the amino groups of aminoglycosides and the phosphate backbone of RNA. In the neomycin-aptamer complex, the 6 -amino group on ring I interacts with the phosphate backbone. Paromomycin, in which the 6 position of ring I is a hydroxyl group, binds... 

STRUCTURAL COMPARISONS BETWEEN PROKARYOTIC AND EUKARYOTIC RIBOSOMAL DECODING A SITES FREE AND COMPLEXED WITH AMINOGLYCOSIDES... 

In aminoglycoside-treated animals, the cells can be led to canonical apop-totic death through activation of caspases. Caspase-9 forms an apoptosome complex with cytochrome c and APAF-1 and leads to apoptosis through activation of caspase-3. Aminoglycosides activate caspases in auditory structures conversely, inhibition of caspase activity successfully blocks neomycin-induced vestibulotoxicity. In contrast, apoptotic markers were essentially absent in a mouse model of chronic kanamycin ototoxicity where death of auditory sensory cells ensued via cathepsins. The activation of cathepsin D was accompanied by the nuclear translocation of endonuclease G, necrotic cleavage of PARP, and activation of p,-calpain, all facets of necrotic cell death. 

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

Forming complexes with organic ligands the example of aminoglycosides... 

Streptomycin, gentamicin, and other aminoglycosides interfere with assembly of the SOS initiation complex and promote incorrect base pairing. 

Kanamycin is an aminoglycoside complex produced by Streptomyces ka-namyceticus. It is comprised of three components, kanamycin A being the major component and kanamycins B and C minor congeners. Kanamycin is active against many pathogenic bacteria and has been used parenterally for treatment of bovine respiratory disease, mastitis, and other infectious conditions. A popular combination used in horses and cattle with respiratory disease is kanamycin and penicillin G. It is also used orally for treatment of bacterial enteritis because limited absorption occurs after oral administration. 

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