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Chapter 4 : Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination

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Abstract:

Aminoglycoside antibiotics are broad-spectrum bactericidal agents that have predictable pharmacokinetics and are used mainly in the treatment of infections caused by gram-negative aerobic bacilli and some gram positives. Aminoglycoside antibiotics are commonly administered by intramuscular injection but also intravenously in cases of severe infections. The aminoglycoside-modifying enzymes are adenylyltransferases (ANTs), phosphotransferases (APHs), also known as kinases, and acetyltransferases (AACs). The three-dimensional structures of two aminoglycoside O-phosphotransferases, APH(3p)-IIIa, from grampositive cocci, and APH(3p)-IIa, from , have been determined. ANTs catalyze the transfer of an AMP group from the substrate ATP to a hydroxyl group in the aminoglycoside molecule. Acetyltransferases (AACs) belong to the GCN5-related N-acetyltransferase superfamily of proteins, which spans all kingdoms of life and comprises several unrelated kinds of enzymes with a wide variety of functions. The presence of genes coding for aminoglycoside-modifying enzymes within many of these elements permitted them to disseminate at the molecular as well as at the cellular level, contributing to the rise of multiresistant bacteria. Protein kinase inhibitors that disable aminoglycoside-modifying enzymes by targeting the ATP-binding site are showing very promising prospects for their use in combination with aminoglycosides. Antisense oligonucleotide-mediated inhibition of expression of genes coding for aminoglycoside-modifying enzymes shows promise for development as another alternative against resistance.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4

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Mobile Genetic Elements
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Figures

Image of Figure 4.1
Figure 4.1

Sites of modification of APHs. The sites of modification are shown on one of the substrates of each class of APH. The number of subclasses is indicated.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.3
Figure 4.3

Sites of modification of ANTs. The sites of modification are shown on one of the substrates of each class of ANT. The number of subclasses is indicated.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.2
Figure 4.2

Genetic map of the region including resistance genes in the ICE SXT. The region shown is thought to have been inserted within the gene of a precursor in a multistep process ( ). The gene and the fragments of are indicated by lighter gray arrows. Transposase related genes (arrows) or truncated genes (boxes) are shown in gray. Truncated genes are indicated with an apostrophe in their names, e.g., means N-terminal coding part of and means C-terminal coding part of . Antibiotic resistance genes are shown in black. Hatched arrows show genes with other or unknown functions. The DNA fragment identical to RSF1010 is indicated.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.4
Figure 4.4

Genetic maps of variable regions of integrons including AAC protein fusions. The black dots indicate the loci in each gene cassette. Gene fusions are shown as black arrows. The genetic maps were redrawn from references , and .

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.5
Figure 4.5

Sites of modification of AACs. The sites of modification are shown on one of the substrates of each class of AAC. The number of subclasses is indicated.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.6
Figure 4.6

N-terminal portions of AAC(6′)-Ib variants. Alignment of the N-terminal amino acid sequences of several AAC(6′)-Ib variants. The accession numbers of the proteins shown are as follows: 1, M55547; 2, AF202035 (S at position 90), L25617 (S90), AF302086 (S90), U90945 (L at position 90), AJ311891 (L90), AF282595 (L90), AF034958 (L90), AJ009820 (L90) (AJ009820 and AF302086 have the last two amino acids different); 3, X60321, AF024602; 4, AF207065, AY033653; 5, AF043381 (S121), U59183 (L121); 6, AY103455; 7, AY136758; 8, Y11948; and 9, Y11947.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.7
Figure 4.7

Visualization of AAC(6′)-Ib-cyan fluorescent protein. Cells containing plasmid pAAC-CFP were stained with the membrane dye FM5-95 and examined on a fluorescent microscope using the appropriate filters to detect FM5-95 or cyan fluorescent protein ( ). Control experiments were done using plasmid pTGS, which encodes a periplasmic protein fused to green fluorescent protein ( ), and pJDT1, which encodes a periplasmic protein fused to green fluorescent protein that accumulates at the poles of the cell ( ).

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.8
Figure 4.8

Genetic map of pJHCMW1 and Tn. (a) The map shows important loci of pJHCMW1:, a target for Xer site-specific recombination ( );, a weak XerD binding site of unknown function ( ); and ( ); and Tn. Tn can be considered to be Tn with the addition of a DNA region harboring three resistance genes. The genetic map of this region is shown in detail including the N terminus of AAC(6′)-Ib, the sites, the gene cassettes, and the nucleotide sequence resulting from the formation of a gene cassette including both and . The arrows on top represent mRNA species. (b) Diagram showing Tn and the region duplicated (boxes) flanking the fragment containing , and in Tn. The dotted arrow inside the box to the right indicates that only a portion of is present on this side.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.9
Figure 4.9

Possible mechanism of generation of the cassette including OXA-9-: illegitimate recombination between an integron containing the - gene cassette immediately following and another one containing an gene cassette ( ).

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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Image of Figure 4.10
Figure 4.10

Determination of mRNA region accessible to antisense oligodeoxynucleotides and reduction of resistance levels by their action. (a) Regions accessible to interaction with antisense oligodeoxynucleotides were determined by a combination of RNase H mapping and computer-generated secondary structure of mRNA. The nucleotides over a black background indicate the regions identified by RNase H mapping (enlarged in the insets) ( ). (b) Selected antisense oligodeoxynucleotides were introduced into cells by electroporation before being exposed to amikacin. The percent CFU per milliliter values represent the fraction of surviving cells compared to the sample that was subjected to electroporation without adding oligodeoxynucleotides ( ). S, sense oligodeoxynucleotides. The sequences of the oligodeoxynucleotides 3, 6, 7, 12, and 13 can be found in reference . values (=3) were calculated with respect to the control sense oligodeoxynucleotides (ODN). values of <0.05 are statistically significant.

Citation: Tolmasky M. 2007. Aminoglycoside-Modifying Enzymes: Characteristics, Localization, and Dissemination, p 35-52. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch4
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References

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1. Ainsa, J. A.,, E. Perez,, V. Pelicic,, F. X. Berthet,, B. Gicquel, and, C. Martin. 1997. Aminoglycoside 2′-N-acetyltransfer-ase genes are universally present in mycobacteria: chara c-terization of the aac(2p)-Ic gene from Mycobacterium tuberculosis and the aac(2p)-Id gene from Mycobacterium smegmatis. Mol. Microbiol. 24:431441.
2. Aires, J. R.,, T. Kohler,, H. Nikaido, and, P. Plesiat. 1999. Involvement of an active efflux system in the natural resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob. Agents Chemother. 43:26242628.
3. Angus-Hill, M. L.,, R. N. Dutnall,, S. T. Tafrov,, R. Stern-glanz, and, V. Ramakrishnan. 1999. Crystal structure of the histone acetyltransferase Hpa2: a tetrameric member of the Gcn5-related N-acetyltransferase superfamily. J. Mol. Biol. 294:13111325.
4. Azucena, E., and, S. Mobashery. 2001. Aminoglycoside-modifying enzymes: mechanisms of catalytic processes and inhibition. Drug. Resist. Updat. 4:106117.
5. Beaber, J.,, B. Hochhut, and, M. K. Waldor. 2004. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427:7274.
6. Beauclerk, A. A., and, E. Cundliffe. 1987. Sites of action of two ribosomal RNA methylases responsible for resistance to aminoglycosides. J. Mol. Biol. 193:661671.
7. Boehr, D. D.,, A. R. Farley,, G. D. Wright, and, J. R. Cox. 2002. Analysis of the pi-pi stacking interactions between the aminoglycoside antibiotic kinase APH(3′)-IIIa and its nucleotide ligands. Chem. Biol. 9:12091217.
8. Boehr, D. D.,, S. I. Jenkins, and, G. D. Wright. 2003. The molecular basis of the expansive substrate specificity of the antibiotic resistance enzyme aminoglycoside acetyltransferase-6′-aminoglycoside phosphotransferase-2″. The role of ASP-99 as an active site base important for acetyl transfer. J. Biol. Chem. 278:1287312880.
9. Boltner, D.,, C. MacMahon,, J. T. Pembroke,, P. Strike, and, A. M. Osborn. 2002. R391: a conjugative integrating mosaic comprised of phage, plasmid, and transposon elements. J. Bacteriol. 184:51585169.
10. Brodersen, D. E.,, W. M. Clemons, Jr.,, A. P. Carter,, R. J. Morgan-Warren,, B. T. Wimberly, and, V. Ramakrishnan. 2000. The structural basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103:11431154.
11. Bryan, L., and, H. van der Elzen. 1977. Effects of membrane-energy mutations and cations on streptomycin and gentamicin accumulation by bacteria: a model for entry of streptomycin and gentamicin in susceptible and resistant bacteria. Antimicrob. Agents Chemother. 12:163177.
12. Burk, D. L., and, A. M. Berghuis. 2002. Protein kinase inhibitors and antibiotic resistance. Pharmacol. Ther. 93:283292.
13. Burk, D. L.,, N. Ghuman,, L. E. Wybenga-Groot, and, A. M. Berghuis. 2003. X-ray structure of the AAC(6′)-Ii antibiotic resistance enzyme at 1.8 A resolution; examination of oligomeric arrangements in GNAT superfamily members. Protein Sci. 12:426437.
14. Burrus, V., and, M. K. Waldor. 2004. Formation of SXT tandem arrays and SXT-R391 hybrids. J. Bacteriol. 186:26362645.
15. Burrus, V., and, M. K. Waldor. 2004. Shaping bacterial genomes with integrative and conjugative elements. Res. Microbiol. 155:376386.
16. Cameron, F. H.,, D. J. Groot Obbink,, V. P. Ackerman, and, R. M. Hall. 1986. Nucleotide sequence of the AAD(2″) ami-noglycoside adenylyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538-1 and dhfrII in R388. Nucleic Acids Res. 14:86258635.
17. Cannon, P. M., and, P. Strike. 1992. Complete nucleotide sequence and gene organization of plasmid NTP16. Plasmid 27:220230.
18. Carter, A. P.,, W. M. Clemons,, D. E. Brodersen,, R. J. Morgan-Warren,, B. T. Wimberly, and, V. Ramakrishnan. 2000. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407:340348.
19. Casin, I.,, F. Bordon,, P. Bertin,, A. Coutrot,, I. Podglajen,, R. Brasseur, and, E. Collatz. 1998. Aminoglycoside 6′-N-acetyltransferase variants of the Ib type with altered substrate profile in clinical isolates of Enterobacter cloacae and Citrobacter freundii. Antimicrob. Agents Chemother. 42:209215.
20. Casin, I.,, B. Hanau-Bercot,, I. Podglajen,, H. Vahaboglu, and, E. Collatz. 2003. Salmonella enterica serovar Typhimurium bla(PER-1)-carrying plasmid pSTI1 encodes an extended-spectrum aminoglycoside 6′-N-acetyltransferase of type Ib. Antimicrob. Agents Chemother. 47:697703.
21. Centron, D., and, P. H. Roy. 1998. Characterization of the 6′-N-aminoglycoside acetyltransferase gene aac(6p)-Iq from the integron of a natural multiresistance plasmid. Antimicrob. Agents Chemother. 42:15061508.
22. Centron, D., and, P. H. Roy. 2002. Presence of a group II intron in a multiresistant Serratia marcescens strain that harbors three integrons and a novel gene fusion. Antimicrob. Agents Chemother. 46:14021409.
23. Chamorro, R. M.,, L. A. Actis,, J. H. Crosa, and, M. E. Tolmasky. 1990. Dissemination of plasmid-mediated ami-kacin resistance among pathogenic Klebsiella pneumoniae. Medicina (Buenos Aires) 50:543547.
24. Chang, A. C. Y., and, S. N. Cohen. 1978. Construction and characterization of amplifiable multicopy DNA cloning vehicles derived from the P15A cryptic miniplasmid. J. Bacteriol. 134:11411156.
25. Chavideh, R.,, S. Sholly,, D. Panaite, and, M. E. Tolmasky. 1999. Effects of F171 mutations in the 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] enzyme on susceptibility to aminogly-cosides. Antimicrob. Agents Chemother. 43:28112812.
26. Chow, J. W.,, V. Kak,, I. You,, S. J. Kao,, J. Petrin,, D. B. Clewell,, S. A. Lerner,, G. H. Miller, and, K. J. Shaw. 2001. Aminoglycoside resistance genes aph(2q)-Ib and aac(6p)-Im detected together in strains of both Escherichia coli and Enterococcus faecium. Antimicrob. Agents Chemother. 45:26912694.
27. Danese, P. N., and, T. J. Silhavy. 1998. Targeting and assembly of periplasmic and outer-membrane proteins in Escherichia coli. Annu. Rev. Genet. 32:5994.
28. Davis, B. D. 1987. Mechanism of bactericidal action of aminoglycosides. Microbiol. Rev. 51:341350.
29. Dery, K. J.,, R. Chavideh,, V. Waters,, R. Chamorro,, L. S. Tolmasky, and, M. E. Tolmasky. 1997. Characterization of the replication and mobilization regions of the multiresistance Klebsiella pneumoniae plasmid pJHCMW1. Plasmid 38:97105.
30. Dery, K. J.,, B. Soballe,, M. S. Witherspoon,, D. Bui,, R. Koch,, D. J. Sherratt, and, M. E. Tolmasky. 2003. The aminoglycoside 6′-N-acetyltransferase type Ib encoded by Tn1331 is evenly distributed within the cell’s cytoplasm. Antimicrob. Agents Chemother. 47:28972902.
31. Dhillon, J.,, R. Fielding,, J. Adler-Moore,, R. L. Goodall, and, D. Mitchison. 2001. The activity of low-clearance liposomal amikacin in experimental murine tuberculosis. J. Antimi-crob. Chemother. 48:869876.
32. Doi, Y.,, J. Wachino,, K. Yamane,, N. Shibata,, T. Yagi,, K. Shibayama,, H. Kato, and, Y. Arakawa. 2004. Spread of novel aminoglycoside resistance gene aac(6’)-Iad among Acinetobacter clinical isolates in Japan. Antimicrob. Agents Chemother. 48:20752080.
33. Doi, Y.,, K. Yokoyama,, K. Yamane,, J. Wachino,, N. Shibata,, T. Yagi,, K. Shibayama,, H. Kato, and, Y. Arakawa. 2004. Plasmid-mediated 16S rRNA methylase in Serratia marcescens conferring high-level resistance to aminoglycosides. Antimicrob. Agents Chemother. 48:491496.
34. Doublet, B.,, F. Weill,, L. Fabre,, E. Chaslus-Dancla, and, A. Cloeckaert. 2004. Variant Salmonella genomic island 1 antibiotic resistance gene cluster containing a novel 3′-N-aminoglycoside acetyltransferase gene cassette, aac(3)-Id, in Salmonella enterica serovar Newport. Antimicrob. Agents Chemother. 48:38063812.
35. Dubois, V.,, L. Poirel,, C. Marie,, C. Arpin,, P. Nordmann, and, C. Quentin. 2002. Molecular characterization of a novel class 1 integron containing bla(GES-1) and a fused product of aac3-Ib/aac6’-Ib’ gene cassettes in Pseudomonas aerugi-nosa. Antimicrob. Agents Chemother. 46:638645.
36. Dunant, P.,, M. C. Walter,, G. Karpati, and, H. Lochmuller. 2003. Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle. Muscle Nerve 27:624627.
37. Dyda, F.,, D. C. Klein, and, A. B. Hickman. 2000. GCN5-related N-acetyltransferases: a structural overview. Annu. Rev. Biophys. Biomol. Struct. 29:81103.
38. Ferretti, J. J.,, K. S. Gilmore, and, P. Courvalin. 1986. Nucle-otide sequence analysis of the gene specifying the bifunctional 6′-aminoglycoside acetyltransferase 2″-aminoglycoside phosphotransferase enzyme in Streptococcus faecalis and identification and cloning of gene regions specifying the two activities. J. Bacteriol. 167:631638.
39. Fourmy, D.,, M. I. Recht,, S. C. Blanchard, and, J. D. Puglisi. 1996. Structure of the A site of Escherichia coli 16S ribo-somal RNA complexed with an aminoglycoside antibiotic. Science 274:13671371.
40. Fourmy, D.,, M. I. Recht, and, J. D. Puglisi. 1998. Binding of neomycin-class aminoglycoside antibiotics to the A-site of 16 S rRNA. J. Mol. Biol. 277:347362.
41. Fourmy, D.,, S. Yoshizawa, and, J. D. Puglisi. 1998. Paromo-mycin binding induces a local conformational change in the A-site of 16 S rRNA. J. Mol. Biol. 277:333345.
42. Franklin, K., and, A. J. Clarke. 2001. Overexpression and characterization of the chromosomal aminoglycoside 2′-N-acetyltransferase of Providencia stuartii. Antimicrob. Agents Chemother. 45:22382244.
43. Galimand, M.,, P. Courvalin, and, T. Lambert. 2003. Plasmid-mediated high-level resistance to aminoglycosides in Enterobacteriaceae due to 16S rRNA methylation. Antimicrob. Agents Chemother. 47:25652571.
44. Guerry, P.,, J. van Embden, and, S. Falkow. 1974. Molecular nature of two nonconjugative plasmids carrying drug resistance genes. J. Bacteriol. 117:619630.
45. Haddad, J.,, L. P. Kotra,, B. Llano-Sotelo,, C. Kim,, E. F. Azucena, Jr.,, M. Liu,, S. B. Vakulenko,, C. S. Chow, and, S. Mobashery. 2002. Design of novel antibiotics that bind to the ribosomal acyltransfer site. J. Am. Chem. Soc. 124:32293237.
46. Hamilton-Miller, J. M., and, S. Shah. 1995. Activity of the semi-synthetic kanamycin B derivative, arbekacin against methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 35:865868.
47. Hannecart-Pokorni, E.,, F. Depuydt,, L. de Wit,, E. van Bossuyt,, J. Content, and, R. Vanhoof. 1997. Characterization of the 6′-N-aminoglycoside acetyltransferase gene aac(6’)-Im [corrected] associated with a sulI-type integron. Antimicrob. Agents Chemother. 41:314318.
48. Hansson, K.,, O. Skold, and, L. Sundstrom. 1997. Non-palin-dromic attl sites of integrons are capable of site-specific recombination with one another and with secondary targets. Mol. Microbiol. 26:441453.
49. Hickman, A. B.,, M. A. Namboodiri,, D. C. Klein, and, F. Dyda. 1999. The structural basis of ordered substrate binding by serotonin N-acetyltransferase: enzyme complex at 1.8 A resolution with a bisubstrate analog. Cell 97:361369.
50. Hochhut, B.,, Y. Lotfi,, D. Mazel,, S. M. Faruque,, R. Wood-gate, and, M. K. Waldor. 2001. Molecular analysis of antibiotic resistance gene clusters in Vibrio cholerae O139 and O1 SXT constins. Antimicrob. Agents Chemother. 45:29913000.
51. Hocquet, D.,, C. Vogne,, F. El Garch,, A. Vejux,, N. Gotoh,, A. Lee,, O. Lomovskaya, and, P. Plesiat. 2003. MexXY-OprM efflux pump is necessary for adaptive resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob. Agents Chemother. 47:13711375.
52. Hoshi, H.,, S. Aburaki,, S. Iimura,, T. Yamasaki,, T. Naito, and, H. Kawaguchi. 1990. Amikacin analogs with a fluorinated amino acid side chain. J. Antibiot. (Tokyo) 43:858872.
53. Hotta, K.,, A. Sunada,, J. Ishikawa,, S. Mizuno,, Y. Ikeda, and, S. Kondo. 1998. The novel enzymatic 3″-N-acetylation of arbekacin by an aminoglycoside 3-N-acetyltransferase of Streptomyces origin and the resulting activity. J. Antibiot. (Tokyo) 51:735742.
54. Howard, M.,, C. Anderson,, U. Fass,, S. Khatri,, R. Gesteland,, J. Atkins, and, K. Flanigan. 2004. Readthrough of dystro-phin stop codon mutations induced by aminoglycosides. Ann. Neurol. 55:422426.
55. Hutchin, T., and, G. Cortopassi. 1994. Proposed molecular and cellular mechanism for aminoglycoside ototoxicity. Antimicrob. Agents Chemother. 38:25172520.
56. Iida, S.,, J. Meyer,, P. Linder,, N. Goto,, R. Nakaya,, H. J. Reif, and, W. Arber. 1982. The kanamycin resistance transposon Tn2680 derived from the R plasmid Rts1 and carried by phage P1Km has flanking 0.8-kb-long direct repeats. Plasmid 8:187198.
57. Iwanaga, M.,, C. Toma,, T. Miyazato,, S. Insisiengmay,, N. Nakasone, and, M. Ehara. 2004. Antibiotic resistance conferred by a class I integron and SXT constin in Vibrio cholerae O1 strains isolated in Laos. Antimicrob. Agents Chemother. 48:23642369.
58. Kawaguchi, H. 1976. Discovery, chemistry, and activity of amikacin. J. Infect. Dis. 134(Suppl.):S242S248.
59. Kehrenberg, C., and, S. Schwarz. 2002. Nucleotide sequence and organization of plasmid pMVSCS1 from Mannheimia varigena: identification of a multiresistance gene cluster. J. Antimicrob. Chemother. 49:383386.
60. Kotra, L. P.,, J. Haddad, and, S. Mobashery. 2000. aminoglycosides: perspectives on mechanisms of action and resistance and strategies to counter resistance. Antimicrob. Agents Chemother. 44:32493256.
61. Lambert, T.,, M. C. Ploy, and, P. Courvalin. 1994. A spontaneous point mutation in the aac(6’)-Ib’ gene results in altered substrate specificity of aminoglycoside 6′-N-acetyltransferase of a Pseudomonas fluorescens strain. FEMS Microbiol. Lett. 115:297304.
62. Levesque, C.,, L. Piche,, C. Larose, and, P. H. Roy. 1995. PCR mapping of integrons reveals several novel combinations of resistance genes. Antimicrob. Agents Chemother. 39:185191.
63. Liebert, C. A.,, R. M. Hall, and, A. O. Summers. 1999. Trans-poson Tn21, flagship of the floating genome. Microbiol. Mol. Biol. Rev. 63:507522.
64. Lovering, A. M.,, L. O. White, and, D. S. Reeves. 1987. AAC(1): a new aminoglycoside-acetylating enzyme modifying the Cl aminogroup of apramycin. J. Antimicrob. Chemother. 20:803813.
65. Lynch, S.,, R. Gonzalez, and, J. D. Puglisi. 2003. Comparison of X-ray crystal structure of the 30S subunit-antibiotic complex with NMR structure of decoding site oligonucleotide-paromomycin complex. Structure 11:4353.
66. Magnet, S., and, J. S. Blanchard. 2005. Molecular insights into aminoglycoside action and resistance. Chem. Rev. 105:477498.
67. Magnet, S.,, P. Courvalin, and, T. Lambert. 2001. Resistance-nodulation-cell division-type efflux pump involved in ami-noglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob. Agents Chemother. 45:33753380.
68. Magnet, S.,, T. A. Smith,, R. Zheng,, P. Nordmann, and, J. S. Blanchard. 2003. Aminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase. Antimicrob. Agents Chemother. 47:15771583.
69. Meier, A.,, P. Kirschner,, F. C. Bange,, U. Vogel, and, E. C. Bottger. 1994. Genetic alterations in streptomycin-resistant Mycobacterium tuberculosis: mapping of mutations conferring resistance. Antimicrob. Agents Chemother. 38:228233.
70. Mendes, R.,, M. Toleman,, J. Ribeiro,, H. Sader,, R. Jones, and, T. Walsh. 2004. Integron carrying a novel metallo-β-lactamase gene, blaIMP-16, and a fused form of aminoglycoside-resistance gene aac(6’)-30/aac(6’)-Ib: report from the SENTRY antimicrobial surveillance program. Antimicrob. Agents Chemother. 48:46934702.
71. Miller, G. H.,, G. Arcieri,, M. J. Weinstein, and, J. A. Waitz. 1976. Biological activity of netilmicin, a broad-spectrum semisynthetic aminoglycoside antibiotic. Antimicrob. Agents Chemother. 10:827836.
72. Miller, G. H.,, F. J. Sabatelli,, R. S. Hare,, Y. Glupczynski,, P. Mackey,, D. Shlaes,, K. Shimizu,, K. J. Shaw, et al. 1997. The most frequent aminoglycoside resistance mechanisms— changes with time and geographic area: a reflection of aminoglycoside usage patterns? Clin. Infect. Dis. 24(Suppl. 1): S46S62.
73. Mingeot-Leclercq, M. P.,, Y. Glupczynski, and, P. M. Tulkens. 1999. Aminoglycosides: activity and resistance. Antimicrob. Agents Chemother. 43:727737.
74. Mingeot-Leclercq, M. P., and, P. M. Tulkens. 1999. aminoglycosides: nephrotoxicity. Antimicrob. Agents Chemother. 43:10031012.
75. Moore, R. A.,, D. DeShazer,, S. Reckseidler,, A. Weissman, and, D. E. Woods. 1999. Efflux-mediated aminoglycoside and macrolide resistance in Burkholderia pseudomallei. Antimicrob. Agents Chemother. 43:465470.
76. Mulvey, M.,, D. Boyd,, L. Baker,, O. Mykytczuk,, E. Resi,, M. Asensi,, D. Rodrigues, and, L. Ng. 2004. Characterization of a Salmonella enterica serovar Agona strain harbouring a class 1 integron containing novel OXA-type β-lactamase (blaOXA-53) and 6′-N-aminoglycoside acetyltransferase genes [aac(6’)-I30]. J. Antimicrob. Chemother. 54:354359.
77. Neuwald, A. F., and, D. Landsman. 1997. GCN5-related his-tone N-acetyltransferases belong to a diverse superfamily that includes the yeast SPT10 protein. Trends Biochem. Sci. 22:154155.
78. Novick, R. P.,, R. C. Clowes,, S. N. Cohen,, R. Curtiss III,, N. Datta, and, S. Falkow. 1976. Uniform nomenclature for bacterial plasmids: a proposal. Bacteriol. Rev. 40:168189.
79. Nurizzo, D.,, S. C. Shewry,, M. H. Perlin,, S. A. Brown,, J. N. Dholakia,, R. L. Fuchs,, T. Deva,, E. N. Baker, and, C. A. Smith. 2003. The crystal structure of aminoglycoside-3′-phosphotransferase-IIa, an enzyme responsible for antibiotic resistance. J. Mol. Biol. 327:491506.
80. Oka, A.,, H. Sugisaki, and, M. Takanami. 1981. Nucleotide sequence of the kanamycin resistance transposon Tn903. J. Mol. Biol. 147:217226.
81. Over, U.,, D. Gur,, S. Unal, and, G. H. Miller. 2001. The changing nature of aminoglycoside resistance mechanisms and prevalence of newly recognized resistance mechanisms in Turkey. Clin. Microbiol. Infect. 7:470478.
82. Panaite, D. M., and, M. E. Tolmasky. 1998. Characterization of mutants of the 6′-N-acetyltransferase encoded by the multiresistance transposon Tn1331: effect of Phen171-to-Leu171 and Tyr80-to-Cys80 substitutions. Plasmid 39:123133.
83. Parent, R., and, P. H. Roy. 1992. The chloramphenicol acetyltransferase gene of Tn2424: a new breed of cat. J. Bacteriol. 174:28912897.
84. Pechere, J. C., and, R. Dugal. 1979. Clinical pharmacokine-tics of aminoglycoside antibiotics. Clin. Pharmacokinet. 4:170199.
85. Perlin, M. H., and, S. A. Lerner. 1981. Localization of an amikacin 3′-phosphotransferase in Escherichia coli. J. Bacteriol. 147:320325.
86. Peters, J. E., and, N. L. Craig. 2001. Tn7: smarter than we thought. Nat. Rev. Mol. Cell Biol. 2:806814.
87. Pfister, P.,, M. Risch,, D. E. Brodersen, and, E. C. Bottger. 2003. Role of 16S rRNA helix 44 in ribosomal resistance to hygromycin B. Antimicrob. Agents Chemother. 47:14961502.
88. Pham, H.,, K. J. Dery,, D. J. Sherratt, and, M. E. Tolmasky. 2002. Osmoregulation of dimer resolution at the plasmid pJHCMW1 mwr locus by Escherichia coli XerCD recombination. J. Bacteriol. 184:16071616.
89. Poirel, L.,, T. Lambert,, S. Turkoglu,, E. Ronco,, J. Gaillard, and, P. Nordmann. 2001. Characterization of Class 1 integrons from Pseudomonas aeruginosa that contain the bla(VIM-2) carbapenem-hydrolyzing β-lactamase gene and of two novel aminoglycoside resistance gene cassettes. Antimicrob. Agents Chemother. 45:546552.
90. Politano, L.,, G. Nigro,, V. Nigro,, G. Piluso,, S. Papparella,, O. Paciello, and, L. I. Comi. 2003. Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol. 22:1521.
91. Poux, A. N.,, M. Cebrat,, C. M. Kim,, P. A. Cole, and, R. Marmorstein. 2002. Structure of the GCN5 histone acetyl-transferase bound to a bisubstrate inhibitor. Proc. Natl. Acad. Sci. USA 99:1406514070.
92. Rather, P. N.,, H. Munayyer,, P. A. Mann,, R. S. Hare,, G. H. Miller, and, K. J. Shaw. 1992. Genetic analysis of bacterial acetyltransferases: identification of amino acids determining the specificities of the aminoglycoside 6′-N-acetyltransferase Ib and IIa proteins. J. Bacteriol. 174:31963203.
93. Rather, P. N.,, E. Orosz,, K. J. Shaw,, R. Hare, and, G. Miller. 1993. Characterization and transcriptional regulation of the 2′-N-acetyltransferase gene from Providencia stuartii. J. Bacteriol. 175:64926498.
94. Recchia, G. D., and, R. M. Hall. 1995. Gene cassettes: a new class of mobile element. Microbiology 141(Pt. 12):30153027.
95. Riccio, M. L.,, J. D. Docquier,, E. Dell’Amico,, F. Luzzaro,, G. Amicosante, and, G. M. Rossolini. 2003. Novel 3-N-aminoglycoside acetyltransferase gene, aac(3)-Ic, from a Pseudomonas aeruginosa integron. Antimicrob. Agents Chemother. 47:17461748.
96. Riccio, M. L.,, N. Franceschini,, L. Boschi,, B. Caravelli,, G. Cornaglia,, R. Fontana,, G. Amicosante, and, G. M. Rosso-lini. 2000. Characterization of the metallo-β-lactamase determinant of Acinetobacter baumannii AC-54/97 reveals the existence of bla(IMP) allelic variants carried by gene cassettes of different phylogeny. Antimicrob. Agents Chemother. 44:12291235.
97. Rice, L.,, D. Sahm, and, R. Bonomo. 2003. Mechanisms of resistance to antibacterial agents, p. 10741101. In P. Murray,, E. Baron,, J. Jorgensen,, M. Pfaller, and, R. Yolken (ed.), Manual of Clinical Microbiology, vol. 1. ASM Press, Washington, D.C.
98. Robicsek, A.,, J. Strahilevitz,, G. Jacoby,, M. Macielag,, D. Abbanat,, C. Park,, K. Bush, and, D. Hooper. Fluoroquino-lone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat. Med. 12:8387.
99. Rosenberg, E. Y.,, D. Ma, and, H. Nikaido. 2000. AcrD of Escherichia coli is an aminoglycoside efflux pump. J. Bacte-riol. 182:17541756.
100. Rudant, E.,, P. Courvalin, and, T. Lambert. 1997. Loss of intrinsic aminoglycoside resistance in Acinetobacter haemolyticus as a result of three distinct types of alterations in the aac(6p)-Ig gene, including insertion of IS17. Antimicrob. Agents Chemother. 41:26462651.
101. Sakon, J.,, H. H. Liao,, A. M. Kanikula,, M. M. Benning,, I. Rayment, and, H. M. Holden. 1993. Molecular structure of kanamycin nucleotidyltransferase determined to 3.0-A resolution. Biochemistry 32:1197711984.
102. Salipante, S. J., and, B. G. Hall. 2003. Determining the limits of the evolutionary potential of an antibiotic resistance gene. Mol. Biol. Evol. 20:653659.
103. Sarno, R.,, H. Ha,, N. Weinsetel, and, M. E. Tolmasky. 2003. Inhibition of aminoglycoside 6′-N-acetyltransferase type Ib-mediated amikacin resistance by antisense oligodeoxynucle-otides. Antimicrob. Agents Chemother. 47:32963304.
104. Sarno, R.,, G. McGillivary,, D. J. Sherratt,, L. A. Actis, and, M. E. Tolmasky. 2002. Complete nucleotide sequence of Klebsiella pneumoniae multiresistance plasmid pJHCMW1. Antimicrob. Agents Chemother. 46:34223427.
105. Scaglione, F.,, S. Dugnani,, G. Demartini,, M. M. Arcidi-acono,, C. E. Cocuzza, and, F. Fraschini. 1995. Bactericidal kinetics of an in vitro infection model of once-daily ceftriaxone plus amikacin against gram-positive and gram-negative bacteria. Chemotherapy 41:239246.
106. Shaw, K. J.,, H. Munayyer,, P. N. Rather,, R. S. Hare, and, G. H. Miller. 1993. Nucleotide sequence analysis and DNA hybridization studies of the ant(4p)-IIa gene from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 37:708714.
107. Shaw, K. J.,, P. N. Rather,, R. S. Hare, and, G. H. Miller. 1993. Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol. Rev. 57:138163.
108. Shaw, K. J., and, G. D. Wright. 2000. Aminoglycoside resistance in gram-positive bacteria, p. 635646. In V. Fischetti,, R. Novick,, J. Ferretti,, D. Portnoy, and, J. Rood (ed.), Gram-Positive Pathogens. ASM Press, Washington, D.C.
109. Shmara, A.,, N. Weinsetel,, K. J. Dery,, R. Chavideh, and, M. E. Tolmasky. 2001. Systematic analysis of a conserved region of the aminoglycoside 6′-N-acetyltransferase type Ib. Antimicrob. Agents Chemother. 45:32873292.
110. Sucheck, S.,, A. Wong,, K. Koeller,, D. Boher,, K. Draker,, P. Sears, and, G. Wright. 2000. Design of bifunctional antibiotics that target bacterial rRNA and inhibit resistance-causing enzymes. J. Am. Chem. soc. 122:52305231.
111. Taber, H. W.,, J. P. Mueller,, P. F. Miller, and, A. S. Arrow. 1987. Bacterial uptake of aminoglycoside antibiotics. Micro-biol. Rev. 51:439457.
112. Tauch, A.,, S. Krieft,, J. Kalinowski, and, A. Puhler. 2000. The 51,409-bp R-plasmid pTP10 from the multiresistant clinical isolate Corynebacterium striatum M82B is composed of DNA segments initially identified in soil bacteria and in plant, animal, and human pathogens. Mol. Gen. Genet. 263:111.
113. Taylor, L. A., and, R. E. Rose. 1988. A correction in the nucleotide sequence of the Tn903 kanamycin resistance determinant in pUC4K. Nucleic Acids Res. 16:358.
114. Tenover, F. C. 2001. Development and spread of bacterial resistance to antimicrobial agents: an overview. Clin. Infect. Dis. 33(Suppl. 3):S108S115.
115. Thomas, J. D.,, R. A. Daniel,, J. Errington, and, C. Robinson. 2001. Export of active green fluorescent protein to the periplasm by the twin-arginine translocase (Tat) pathway in Escherichia coli. Mol. Microbiol. 39:4753.
116. Thompson, P. R.,, D. D. Boehr,, A. M. Berghuis, and, G. D. Wright. 2002. Mechanism of aminoglycoside antibiotic kinase APH(3′)-IIIa: role of the nucleotide positioning loop. Biochemistry 41:70017007.
117. Tolmasky, M. E. 2000. Bacterial resistance to aminoglycosides and β-lactams: the Tn1331 transposon paradigm. Front. Biosci. 5:D20D29.
118. Tolmasky, M. E. 1990. Sequencing and expression of aadA, bla, and tnpR from the multiresistance transposon Tn1331. Plasmid 24:218226.
119. Tolmasky, M. E.,, R. M. Chamorro,, J. H. Crosa, and, P. M. Marini. 1988. Transposon-mediated amikacin resistance in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 32:14161420.
120. Tolmasky, M. E., and, J. H. Crosa. 1993. Genetic organization of antibiotic resistance genes (aac(6p)-Ib, aadA, and oxa9) in the multiresistance transposon Tn1331. Plasmid 29:3140.
121. Tolmasky, M. E., and, J. H. Crosa. 1987. Tn1331, a novel multiresistance transposon encoding resistance to amikacin and ampicillin in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 31:19551960.
122. Vakulenko, S. B., and, S. Mobashery. 2003. Versatility of aminoglycosides and prospects for their future. Clin. Micro-biol. Rev. 16:430450.
123. Vanhoof, R.,, E. Hannecart-Pokorni, and, J. Content. 1998. Nomenclature of genes encoding aminoglycoside-modifying enzymes. Antimicrob. Agents Chemother. 42: 483.
124. Vazquez-Laslop, N.,, H. Lee,, R. Hu, and, A. A. Neyfakh. 2001. Molecular sieve mechanism of selective release of cytoplasmic proteins by osmotically shocked Escherichia coli. J. Bacteriol. 183:23992404.
125. Vetting, M.,, S. L. Roderick,, S. Hegde,, S. Magnet, and, J. S. Blanchard. 2003. What can structure tell us about in vivo function? The case of aminoglycoside-resistance genes. Biochem. Soc. Trans. 31:520522.
126. Vetting, M. W.,, S. S. Hegde,, F. Javid-Majd,, J. S. Blanchard, and, S. L. Roderick. 2002. Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates. Nat. Struct. Biol. 9:653658.
127. Vicens, Q., and, E. Westhof. 2001. Crystal structure of paromomycin docked into the eubacterial ribosomal decoding A site. Structure 9:647658.
128. Vicens, Q., and, E. Westhof. 2003. Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes: an analysis of x-ray crystal structures. Biopolymers 70:4257.
129. Vliegenthart, J. S.,, P. A. Ketelaarvan Gaalen,, J. Eelhart, and, J. A. van de Klundert. 1991. Localisation of the aminoglycoside-(3)-N-acetyltransferase isoenzyme II in Escherichia coli. FEMS Microbiol. Lett. 65:101105.
130. Waldor, M. K.,, H. Tschape, and, J. J. Mekalanos. 1996. A new type of conjugative transposon encodes resistance to sulfamethoxazole, trimethoprim, and streptomycin in Vibrio cholerae O139. J. Bacteriol. 178:41574165.
131. Walker, R. J., and, G. G. Duggin. 1988. Drug nephrotoxicity. Annu. Rev. Pharmacol. Toxicol. 28:331345.
132. Walter, F.,, Q. Vicens, and, E. Westhof. 1999. aminoglycoside-RNA interactions. Curr. Opin. Chem. Biol. 3:694704.
133. Westbrock-Wadman, S.,, D. R. Sherman,, M. J. Hickey,, S. N. Coulter,, Y. Q. Zhu,, P. Warrener,, L. Y. Nguyen,, R. M. Shawar,, K. R. Folger, and, C. K. Stover. 1999. Characterization of a Pseudomonas aeruginosa efflux pump contributing to aminoglycoside impermeability. Antimicrob. Agents Chemother. 43:29752983.
134. White, D. G.,, K. Maneewannakul,, E. von Hofe,, M. Zill-man,, W. Eisenberg,, A. K. Field, and, S. B. Levy. 1997. Inhibition of the multiple antibiotic resistance (mar) operon in Escherichia coli by antisense DNA analogs. Antimicrob. Agents Chemother. 41:26992704.
135. Wolf, E.,, A. Vassilev,, Y. Makino,, A. Sali,, Y. Nakatani, and, S. K. Burley. 1998. Crystal structure of a GCN5-related N-acetyltransferase: Serratia marcescens aminoglycoside 3-N-acetyltransferase. Cell 94:439449.
136. Woloj, M.,, M. E. Tolmasky,, M. C. Roberts, and, J. H. Crosa. 1986. Plasmid-encoded amikacin resistance in multi-resistant strains of Klebsiella pneumoniae isolated from neonates with meningitis. Antimicrob. Agents Chemother. 29:315319.
137. Wright, G. D., and, P. R. Thompson. 1999. Aminoglycoside phosphotransferases: proteins, structure, and mechanism. Front. Biosci. 4:D9D21.
138. Wybenga-Groot, L. E.,, K. Draker,, G. D. Wright, and, A. M. Berghuis. 1999. Crystal structure of an aminoglycoside 6′-N-acetyltransferase: defining the GCN5-related N-acetyltransferase superfamily fold. Structure 7:497507.
139. Yamane, K.,, Y. Doi,, K. Yokoyama,, T. Yagi,, H. Kurokawa,, N. Shibata,, K. Shibayama,, H. Kato, and, Y. Arakawa. 2004. Genetic environments of the rmtA gene in Pseudomonas aeruginosa clinical isolates. Antimicrob. Agents Chemother. 48:20692074.
140. Yao, J., and, R. Moellering. 2003. Antibacterial agents, p. 10311073. In P. Murray,, E. Baron,, J. Jorgensen,, M. Pfaller, and, R. Yolken (ed.), Manual of Clinical Microbiology, vol. 1. ASM Press, Washington, D.C.
141. Yoshizawa, S.,, D. Fourmy,, R. G. Eason, and, J. D. Puglisi. 2002. Sequence-specific recognition of the major groove of RNA by deoxystreptamine. Biochemistry 41:62636270.
142. Yoshizawa, S.,, D. Fourmy, and, J. D. Puglisi. 1998. Structural origins of gentamicin antibiotic action. EMBO J. 17:64376448.

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