Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.

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Shi K, Caldwell SJ, Fong DH, Berghuis AM

Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.

Front Cell Infect Microbiol. 2013 Jun 25;3:22. doi: 10.3389/fcimb.2013.00022. eCollection 2013.

PubMed ID

23805415 [ View in PubMed

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Abstract

Aminoglycosides are a class of antibiotics with a broad spectrum of antimicrobial activity. Unfortunately, resistance in clinical isolates is pervasive, rendering many aminoglycosides ineffective. The most widely disseminated means of resistance to this class of antibiotics is inactivation of the drug by aminoglycoside-modifying enzymes (AMEs). There are two principal strategies to overcoming the effects of AMEs. The first approach involves the design of novel aminoglycosides that can evade modification. Although this strategy has yielded a number of superior aminoglycoside variants, their efficacy cannot be sustained in the long term. The second approach entails the development of molecules that interfere with the mechanism of AMEs such that the activity of aminoglycosides is preserved. Although such a molecule has yet to enter clinical development, the search for AME inhibitors has been greatly facilitated by the wealth of structural information amassed in recent years. In particular, aminoglycoside phosphotransferases or kinases (APHs) have been studied extensively and crystal structures of a number of APHs with diverse regiospecificity and substrate specificity have been elucidated. In this review, we present a comprehensive overview of the available APH structures and recent progress in APH inhibitor development, with a focus on the structure-guided strategies.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ribostamycin	Aminoglycoside 2'-N-acetyltransferase	Protein	Mycobacterium tuberculosis	Unknown	Substrate	Details