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Circumventing Aminoglycoside Inhibition by 3 -Aminoglycoside O-Phosphotransferase

Two main principles are followed in the search of ways to circumvent inacti-vation of aminoglycosides by modifying enzymes. The first involves abolishing the resistance mechanism such that antibacterial activity can be restored. The second approach requires the development of compounds that are effective inhibitors of bacterial protein translation and can also evade resistant mechanisms. Most of these studies have been done with the phos-photransferase class of enzyme due to the amount of information available. Many compounds were developed based on the binding properties of the aminoglycosides, as well as on the kinetic mechanism of the aminoglyco-side-modifying enzymes. Additionally, structural information has added much insight in the development of aminoglycoside derivatives and inhibitors targeted at the cofactor binding site or the whole binding cleft.

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