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Chapter 2 : Aminoglycoside Antibiotics

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Aminoglycoside Antibiotics, Page 1 of 2

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Abstract:

“Aminoglycoside (AG) antibiotics” is a large group of antibiotics that inhibit protein biosynthesis in bacteria. This chapter focuses on the general aspects of AG antibiotics and associated resistance factors with particular attention to the literature and developments between 2000 and 2003. AG antibiotics are effective against both gram-negative and gram-positive bacteria. Popular AG antibiotics such as neomycins, paromomycin, kanamycins, gentamicins tobramycin, and amikacin belong to the group of amino-glycosides that contain the 2-deoxystreptamine core moiety. There are several reviews on the activities, structure, resistance, and side effects of AGs. The chapter talks about the molecular mechanism of action, resistance to AGs, epidemiology, and clinical importance. The enzymatic mechanism is the most important one due to its prevalence among various pathogenic bacteria. ANTs catalyze the modification of an AG via transfer of a nucleotide monophosphate (NMP) from a corresponding nucleotide triphosphate (NTP). Among ANTs, ANT(4') and ANT(2')-I are the most mechanistically studied ANTs. ANTs also appear to be part of bifunctional enzymes, which would possess two different types of AG-modifying activities. Members of AACs do not have close sequence homologies to the other two classes of AG-modifying enzymes, ANTs and APHs. Understanding complex ecological, biochemical, and molecular origins of antimicrobial resistance mechanisms in relation to antibiotics, their development, and their dissemination in addition to developing newer inhibitors is important to continue to use effective drugs such as AGs in the clinic.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2

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Bacterial Proteins
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Hygromycin B
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Acetyl Coenzyme A
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Electron Transport System
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Figure 2.1

Aminoglycoside antibiotics.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.2

Structures of aminoglycosides complexed with rRNAs. (A) Eukaryotic decoding region A-site RNA complexed with paromomycin. (B) Crystal structure of tobramycin bound to the eubacterial 16S rRNA A site. (C) Gentamicin C1A bound at the A-site. The rRNA backbone is represented as a ribbon and the aminoglycoside is shown in ball-and-stick representation (panels A and B) or in space-fill model (panel C).

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.3

Aminoglycoside antibiotic paromomycin bound at the A-site of an RNA oligonucleotide that contains the 30S rRNA. (A) Connolly water-accessible surface for the A-site is shown as chicken mesh, and the drug paromomycin is shown as a capped-stick model. The backbone of the RNA is shown as a ribbon. (B) Rings I and II of paromomycin and their interactions with the A-site nucleotides via hydrogen bonds are shown. The backbone of the RNA is shown as a ribbon, paromomycin is shown as capped-stick, and hydrogen bonds are shown by broken lines.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.4

Stereo view of X-ray crystal structure of kanamycin-4′-nucleotidyltransferase (KNT) in complex with kanamycin and ATP. Ribbons represent the backbone of dimeric form of KNT. Kanamycin is shown in ball-and-stick representation and ATP is shown as a capped-stick model. Hydrogen bonds between kanamycin and various residues of the enzyme are shown by broken lines. Magnesium ion is shown as a sphere.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.5

Stereo view of overlap of X-ray structures of AAC(2′)-Ic (each monomer is bound to one CoA molecule) and AAC(6′)-Ii (overlapped onto the monomer on the right). Coenzyme A (CoA) in AAC(2′)-Ic is shown as a capped-stick model, one CoA molecule bound to each monomer. CoA in AAC(6′)-Ii is shown in ball-and-stick representation in the binding site of the enzyme and assumes a conformation very close to that in AAC(2′)-Ic.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.6

(A) X-ray crystal structure of APH(3′)-IIIa shown in ribbon representation. Two monomers are held together via two disulfide bonds (shown by arrows at 6 and 12 o’clock positions). ATP is shown in capped-stick representation. ATP binding sites in each monomer (shown as Connolly water-accessible surfaces) are far from each other. (B) A close view of the kanamycin bound in the active site of APH(3′)-IIa, a negatively charged pocket. The active site is shown as Connolly water-accessible surface. Kanamycin is shown in ball-and-stick representation. Magnesium and sodium ions, shown as spheres, are bound in the active site interacting with the aminoglycoside and the enzyme active site.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.7

Hydrogen bonds between geneticin and various nucleotides in the A-site of the eubacterial 16S rRNA are shown in broken lines. Geneticin is given in capped-stick representation. Critical nucleic bases are shown in capped-stick representation.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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Figure 2.8

Inhibitors of aminoglycoside resistance enzymes.

Citation: Majumder K, Wei L, Annedi S, Kotra L. 2007. Aminoglycoside Antibiotics, p 7-20. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch2
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