Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance

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.

Inhibition of AAC(6′)-Ib-Mediated Resistance to Amikacin in Acinetobacter baumannii by an Antisense Peptide-Conjugated 2′,4′-Bridged Nucleic Acid-NC-DNA Hybrid Oligomer

“…Part of the management of this problem could be the extension of the useful life of existing antibiotics by finding inhibitors of the resistance mechanisms or their expression (30,46,47). Here we tested one of the latest oligonucleotide analogs, a hybrid oligomer composed of 2=,4=-bridged nucleic acid-NC residues and deoxynucleotides conjugated to the permeabilizing peptide (RXR) 4 XB, as an antisense inhibitor of resistance to AMK mediated by AAC(6=)-Ib, one of the most widespread aminoglycoside-modifying enzymes (30,39).…”

Conventional Antibiotics – Revitalized by New Agents

“…This combination is active against KPC-2-producing K. pneumoniae and AmpC- [42]. These data suggest that the commercial development of a universal APH inhibitor may not be feasible.…”

Raf-Kinase Inhibitor Gw5074 Shows Antibacterial Activity Against Methicillin-Resistant Staphylococcus Aureus and Potentiates the Activity of Gentamicin

“…For example, clavulanic acid, tazobactam and sulbactam are β-lactamase inhibitors that have been used successfully in combination with β-lactams antibiotics, and they have prolonged and expanded their effectiveness [6][7][8]. Aminoglycoside, macrolide and lincosamide antibiotics are also susceptible to enzyme-mediated deactivation through phosphorylation by kinases [9][10][11][12][13]. The clinical success of β-lactam/β-lactamase inhibitor combinations suggests that other similar antibiotic/kinase inhibitor strategies might also be u seful.…”