Aminoglycoside Kinases and Antibiotic Resistance

D. H. Fong1 • D. L. Burk1 • A. M. Berghuis2 ())

1 Department of Biochemistry, McGill University, 740 Dr. Penfield Avenue, Montreal, QC, H3A 1A4, Canada

2 Departments of Biochemistry and Microbiology & Immunology, McGill University, 740 Dr. Penfield Avenue, Rm 5202, Montreal, QC, H3A 1A4, Canada [email protected]

1 Introduction 158

2 Aminoglycosides and Aminoglycoside Resistance 158

2.1 Aminoglycoside Antibiotics 158

2.2 Resistance to Aminoglycosides 160

2.3 Aminoglycoside Phosphotransferases 161

3 3'-Aminoglycoside O-Phosphotransferase-IIIa Structure and Similarity to Eukaryotic Protein Kinases 164

3.1 Tertiary Structure 164

3.2 ATP-Binding Site 165

3.3 Aminoglycoside-Binding Site 167

4 Circumventing Aminoglycoside Inhibition by 3'-Aminoglycoside O-Phosphotransferase 168

4.1 Targeting the Aminoglycosides and Their Binding Pocket 169

4.1.1 Removing the Target Functional Group 169

4.1.2 Reducing the Binding Affinity 170

4.1.3 Neamine Derivatives 172

4.1.4 Mechanism-Based Inhibition 174

4.2 Targeting the Nucleotide-Binding Pocket 178

4.3 Exploiting the Bridged Binding Site 180

4.4 Alternative Strategies for Circumventing Antibiotic Resistances 181

5 Conclusions 182

References 183

Abstract The evolution of antibiotic-resistant bacteria represents a serious public health concern. The appearance of strains with resistance to multiple antibiotics threatens to render some infections untreatable by existing drugs. As a result, there is considerable interest in understanding the mechanisms of antibiotic resistance and in identifying ways in which antibiotic resistance can be overcome. Aminoglycoside antibiotics are broad-spectrum bactericidal compounds that are commonly used in the treatment of serious nosocomial infections. They exert their activity by binding to the A-site of the bacterial 30S ribosomal subunit where they impair the fidelity of protein translation. A number of bacterial strains have developed resistance to many aminoglycosides as a result of their acquisition of aminoglycoside-modifying enzymes that inactivate the antibiotic by reducing its affinity for the bacterial ribosome. These modifying enzymes can be classified into three groups according to the identity of the group used to modify the antibiotic substrate—aminoglycoside acetyltransferases, aminoglycoside phosphotransferases (kinases) and aminoglycoside nucleotidyltransferases. One of the best-understood amino-glycoside-modifying enzymes is aminoglycoside 3'-phosphotransferase type Ilia [APH (3')-IIIa]. This enzyme catalyses the transfer of a phosphate moiety from ATP to a range of aminoglycoside substrates. Surprisingly, when the three-dimensional atomic structure of APH (3')-IIIa was determined, it was found to possess striking similarity to eukaryotic protein kinases. Strategies to overcome resistance to aminoglycoside antibiotics are mul-tifaceted and include: (1) novel aminoglycosides that are either not modified, or have low affinity for modifying enzymes, (2) mechanism-based inhibitors that exploit the enzyme's activity, (3) inhibitors of eukaryotic protein kinases that bind in the nucleotide-binding pocket, (4) bridged molecules that interact with both the nucleotide and aminoglycoside binding sites and (5) cationic peptides that resemble protein kinase inhibitors. By pursuing these leads, it is hoped that compounds will be developed that will allow aminoglycoside antibiotics to remain useful components of the physician's armamentarium.

Keywords Aminoglycoside ■ Protein kinase ■ Antibiotic resistance ■ Inhibitor design

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