Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance

Frontiers in Cellular and Infection Microbiology

Volumn 4, Issue JUN, 2013, Pages

  Shi, Kun ^a   Caldwell, Shane J ^a   Fong, Desiree H ^a   Berghuis, Albert M ^a  

^a MCGILL UNIVERSITY   (Canada)

Author keywords

Aminoglycosides; Antibiotic resistance; Drug design; Inhibitor; Kinases; Structure based

Indexed keywords

ACETYL COENZYME A ACYLTRANSFERASE; AMIKACIN; AMINOGLYCOSIDE; AMINOGLYCOSIDE PHOSPHOTRANSFERASE; AMINOGLYCOSIDE PHOSPHOTRANSFERASE INHIBITOR; BETA LACTAM; BUTIROSIN; CIPROFLOXACIN; DIBEKACIN; ENZYME INHIBITOR; GENTAMICIN; HABEKACIN; HYGROMYCIN; ISEPAMICIN; KANAMYCIN; LIVIDOMYCIN; METICILLIN; NEOMYCIN; NETILMICIN; NUCLEOSIDE TRIPHOSPHATE DEPENDENT NUCLEOTIDYLTRANSFERASE; NUCLEOSIDE TRIPHOSPHATE DEPENDENT PHOSPHOTRANSFERASE; NUCLEOTIDYLTRANSFERASE; PAROMOMYCIN; PHOSPHOTRANSFERASE; RIBOSTAMYCIN; SISOMICIN; SPECTINOMYCIN; STREPTOMYCIN; TOBRAMYCIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANTIINFECTIVE AGENT; KANAMYCIN KINASE; INHIBITOR;

ANTIBIOTIC RESISTANCE; BINDING AFFINITY; DRUG DESIGN; ENDOCARDITIS; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; ENZYME SUBSTRATE COMPLEX; HUMAN; MULTIDRUG RESISTANT TUBERCULOSIS; MUTATION; NONHUMAN; PERITONITIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPE; RESPIRATORY TRACT INFECTION; REVIEW; RNA METHYLATION; SEPTICEMIA; SKIN INFECTION; TUBERCULOSIS; ANTAGONISTS AND INHIBITORS; BACTERIA; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; ENZYMOLOGY; ISOLATION AND PURIFICATION; METABOLISM; PROCEDURES; PROTEIN CONFORMATION; BACTERIUM; DRUG ANTAGONISM; DRUG EFFECT; KINASES; METHODOLOGY; STRUCTURE-BASED;

AMINOGLYCOSIDES; ANTI-BACTERIAL AGENTS; BACTERIA; DRUG DISCOVERY; DRUG RESISTANCE, BACTERIAL; ENZYME INHIBITORS; KANAMYCIN KINASE; MODELS, MOLECULAR; PROTEIN CONFORMATION;

AMINOGLYCOSIDES; ANTIBIOTIC RESISTANCE; DRUG DESIGN; INHIBITOR; KINASES; STRUCTURE-BASED;

EID: 84891392748     PISSN: None     EISSN: 22352988     Source Type: Journal    
DOI: 10.3389/fcimb.2013.00022     Document Type: Review

References (137)

1. Alangaden, G. J., Kreiswirth, B. N., Aouad, A., Khetarpal, M., Igno, F. R., Moghazeh, S. L., et al. (1998). Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 42, 1295-1297.
2. Armstrong, E. S., and Miller, G. H. (2010). Combating evolution with intelligent design: the neoglycoside ACHN-490. Curr. Opin. Microbiol. 13, 565-573. doi: 10.1016/j.mib.2010.09.004
3. Badarau, A., Shi, Q., Chow, J. W., Zajicek, J., Mobashery, S., and Vakulenko, S. (2008). Aminoglycoside 2"-phosphotransferase type IIIa from Enterococcus. J. Biol. Chem. 283, 7638-7647. doi: 10.1074/jbc.M709645200
4. Beck, E., Ludwig, G., Auerswald, E. A., Reiss, B., and Schaller, H. (1982). Nucleotide sequence and exact localization of the neomycin phosphotransferase gene from transposon Tn5. Gene 19, 327-336. doi: 10.1016/0378-1119(82)90023-3
5. Begg, E. J., and Barclay, M. L. (1995). Aminoglycosides-50 years on. Br. J. Clin. Pharmacol. 39, 597-603.
6. Berman, J. D., and Fleckenstein, L. (1991). Pharmacokinetic justification of antiprotozoal therapy. Clin. Pharmacokinet. 21, 479-493. doi: 10.2165/00003088-199121060-00007
7. Bilgin, N., Richter, A. A., Ehrenberg, M., Dahlberg, A. E., and Kurland, C. G. (1990). Ribosomal RNA and protein mutants resistant to spectinomycin. EMBO J. 9, 735-739.
8. Boehr, D. D., Draker, K.-A., Koteva, K., Bains, M., Hancock, R. E., and Wright, G. D. (2003). Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes. Chem. Biol. 10, 189-196. doi: 10.1016/S1074-5521(03)00026-7
9. Boehr, D. D., Lane, W. S., and Wright, G. D. (2001). Active site labeling of the gentamicin resistance enzyme AAC(6')-APH(2") by the lipid kinase inhibitor wortmannin. Chem. Biol. 8, 791-800. doi: 10.1016/S1074-5521(01)00051-5
10. Borer, A., Saidel-Odes, L., Riesenberg, K., Eskira, S., Peled, N., Nativ, R., et al. (2009). Attributable mortality rate for carbapenem-resistant Klebsiella pneumoniae bacteremia. Infect. Control Hosp. Epidemiol. 30, 972-976. doi: 10.1086/605922
11. Brenner, S. (1987). Phosphotransferase sequence homology. Nature 329, 21. doi: 10.1038/329021a0
12. Bruinsma, N., Hutchinson, J. M., van den Bogaard, A. E., Giamarellou, H., Degener, J., and Stobberingh, E. E. (2003). Influence of population density on antibiotic resistance. J. Antimicrob. Chemother. 51, 385-390. doi: 10.1093/jac/dkg072
13. Bryan, L. E., Kowand, S. K., and Van Den Elzen, H. M. (1979). Mechanism of aminoglycoside antibiotic resistance in anaerobic bacteria: Clostridium perfringens and Bacteroides fragilis. Antimicrob. Agents Chemother. 15, 7-13. doi: 10.1128/AAC.15.1.7
14. Burk, D. L., Hon, W. C., Leung, A. K., and Berghuis, A. M. (2001). Structural analyses of nucleotide binding to an aminoglycoside phosphotransferase. Biochemistry 40, 8756-8764. doi: 10.1021/bi010504p
15. Caldwell, S. J., and Berghuis, A. M. (2012). Small-angle X-ray scattering analysis of the bifunctional antibiotic resistance enzyme aminoglycoside (6') acetyltransferase-Ie/aminoglycoside (2") phosphotransferase-Ia reveals a rigid solution structure. Antimicrob. Agents Chemother. 56, 1899-1906. doi: 10.1128/AAC.06378-11
16. Caminero, J. A., Sotgiu, G., Zumla, A., and Migliori, G. B. (2010). Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect. Dis. 10, 621-629. doi: 10.1016/S1473-3099(10)70139-0
17. Carlet, J., Jarlier, V., Harbarth, S., Voss, A., Goossens, H., Pittet, D., et al. (2012). Ready for a world without antibiotics. The pensières antibiotic resistance call to action. Antimicrob. Resist. Infect. Control 1, 11. doi: 10.1186/2047-2994-1-11
18. Carter, A. P., Clemons, W. M., Brodersen, D. E., Morgan-Warren, R. J., Wimberly, B. T., and Ramakrishnan, V. (2000). Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407, 340-348. doi: 10.1038/35030019
19. Cass, R. T., Brooks, C. D., Havrilla, N. A., Tack, K. J., Borin, M. T., Young, D., et al. (2011). Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects. Antimicrob. Agents Chemother. 55, 5874-5880. doi: 10.1128/AAC.00624-11
20. Chow, J. W., Zervos, M. J., Lerner, S. A., Thal, L. A., Donabedian, S. M., Jaworski, D. D., et al. (1997). A novel gentamicin resistance gene in Enterococcus. Antimicrob. Agents Chemother. 41, 511-514.
21. Daigle, D. M., Hughes, D. W., and Wright, G. D. (1999). Prodigious substrate specificity of AAC(6')-APH(2"), an aminoglycoside antibiotic resistance determinant in enterococci and staphylococci. Chem. Biol. 6, 99-110. doi: 10.1016/S1074-5521(99)80006-4
22. Daigle, D. M., McKay, G. A., and Wright, G. D. (1997). Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors. J. Biol. Chem. 272, 24755-24758. doi: 10.1074/jbc.272.40.24755
23. Distler, J., Braun, C., Ebert, A., and Piepersberg, W. (1987). Gene cluster for streptomycin biosynthesis in Streptomyces griseus: analysis of a central region including the major resistance gene. Mol. Gen. Genet. 208, 204-210. doi: 10.1007/BF00330443
24. Doi, Y., and Arakawa, Y. (2007). 16S ribosomal RNA methylation: emerging resistance mechanism against aminoglycosides. Clin. Infect. Dis. 45, 88-94. doi: 10.1086/518605
25. Drawz, S. M., and Bonomo, R. A. (2010). Three decades of ß-lactamase inhibitors. Clin. Microbiol. Rev. 23, 160-201. doi: 10.1128/CMR.00037-09
26. Duncan, W. C., Holder, W. R., Roberts, D. P., and Knox, J. M. (1972). Treatment of gonorrhea with spectinomycin hydrochloride: comparison with standard penicillin schedules. Antimicrob. Agents Chemother. 1, 210-214. doi: 10.1128/AAC.1.3.210
27. Ferretti, J. J., Gilmore, K. S., and Courvalin, P. (1986). Nucleotide 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, 631-638.
28. Fong, D. H., and Berghuis, A. M. (2002). Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry. EMBO J. 21, 2323-2331. doi: 10.1093/emboj/21.10.2323
29. Fong, D. H., and Berghuis, A. M. (2009). Structural basis of APH(3')-IIIa-mediated resistance to N1-substituted aminoglycoside antibiotics. Antimicrob. Agents Chemother. 53, 3049-3055. doi: 10.1128/AAC.00062-09
30. Fong, D. H., Lemke, C. T., Hwang, J., Xiong, B., and Berghuis, A. M. (2010). Structure of the antibiotic resistance factor spectinomycin phosphotransferase from Legionella pneumophila. J. Biol. Chem. 285, 9545-9555. doi: 10.1074/jbc.M109.038364
31. Fong, D. H., Xiong, B., Hwang, J., and Berghuis, A. M. (2011). Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor. PLoS ONE 6:e19589. doi: 10.1371/journal.pone.0019589
32. Frase, H., Toth, M., and Vakulenko, S. B. (2012). Revisiting the nucleotide and aminoglycoside substrate specificity of the bifunctional aminoglycoside acetyltransferase(6')-Ie/aminoglycoside phosphotransferase(2")-Ia enzyme. J. Biol. Chem. 287, 43262-43269. doi: 10.1074/jbc.M112.416453
33. Galimand, M., Courvalin, P., and Lambert, T. (2003). Plasmid-mediated high-level resistance to aminoglycosides in Enterobacteriaceae due to 16S rRNA methylation. Antimicrob. Agents Chemother. 47, 2565-2571. doi: 10.1128/AAC.47.8.2565-2571.2003
34. Gilmore, B. F. (2012). Bacteriophages as anti-infective agents: recent developments and regulatory challenges. Expert Rev. Anti Infect. Ther. 10, 533-535. doi: 10.1586/eri.12.30
35. Gonzalez, L. S., and Spencer, J. P. (1998). Aminoglycosides: a practical review. Am. Fam. Physician 58, 1811-1820.
36. Graham, J. C. (2002). Role of aminoglycosides in the treatment of bacterial endocarditis. J. Antimicrob. Chemother. 49, 437-444. doi: 10.1093/jac/49.3.437
37. Gritz, L., and Davies, J. (1983). Plasmid-encoded hygromycin B resistance: the sequence of hygromycin B phosphotransferase gene and its expression in Escherichia coli and Saccharomyces cerevisiae. Gene 25, 179-188. doi: 10.1016/0378-1119(83)90223-8
38. Hancock, R. E. W., and Sahl, H.-G. (2006). Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 24, 1551-1557. doi: 10.1038/nbt1267
39. Hanessian, S., Pachamuthu, K., Szychowski, J., Giguère, A., Swayze, E. E., Migawa, M. T., et al. (2010). Structure-based design, synthesis and A-site rRNA co-crystal complexes of novel amphiphilic aminoglycoside antibiotics with new binding modes: a synergistic hydrophobic effect against resistant bacteria. Bioorg. Med. Chem. Lett. 20, 7097-7101. doi: 10.1016/j.bmcl.2010.09.084
40. Hanks, S. K., and Hunter, T. (1995). The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576-596.
41. Heinzel, P., Werbitzky, O., Distler, J., and Piepersberg, W. (1988). A second streptomycin resistance gene from Streptomyces griseus codes for streptomycin-3"-phosphotransferase. Relationships between antibiotic and protein kinases. Arch. Microbiol. 150, 184-192. doi: 10.1007/BF00425160
42. Herbert, C. J., Giles, I. G., and Akhtar, M. (1983). The sequence of an antibiotic resistance gene from an antibiotic-producing bacterium. Homologies with transposon genes. FEBS Lett. 160, 67-71. doi: 10.1016/0014-5793(83)80937-5
43. Herbert, C. J., Sarwar, M., Ner, S. S., Giles, I. G., and Akhtar, M. (1986). Sequence and interspecies transfer of an aminoglycoside phosphotransferase gene (APH) of Bacillus circulans. Self-defence mechanism in antibiotic-producing organisms. Biochem. J. 233, 383-393.
44. Hidalgo, L., Hopkins, K. L., Gutierrez, B., Ovejero, C. M., Shukla, S., Douthwaite, S., et al. (2013). Association of the novel aminoglycoside resistance determinant RmtF with NDM carbapenemase in Enterobacteriaceae isolated in India and the UK. J. Antimicrob. Chemother. 68, 1543-1550. doi: 10.1093/jac/dkt078
45. Hon, W. C., McKay, G. A., Thompson, P. R., Sweet, R. M., Yang, D. S., Wright, G. D., et al. (1997). Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 89, 887-895. doi: 10.1016/S0092-8674(00)80274-3
46. Hoshiko, S., Nojiri, C., Matsunaga, K., Katsumata, K., Satoh, E., and Nagaoka, K. (1988). Nucleotide-sequence of the ribostamycin phosphotransferase gene and of its control region in Streptomyces ribosidificus. Gene 68, 285-296. doi: 10.1016/0378-1119(88)90031-5
47. Hotta, K., Sunada, A., Ishikawa, J., Mizuno, S., Ikeda, Y., and Kondo, S. (1998). The novel enzymatic 3"-N-acetylation of arbekacin by an aminoglycoside 3-N-acetyltransferase of Streptomyces origin and the resulting activity. J. Antibiot. 51, 735-742. doi: 10.7164/antibiotics.51.735
48. Hotta, K., Zhu, C. B., Ogata, T., Sunada, A., Ishikawa, J., Mizuno, S., et al. (1996). Enzymatic 2'-N-acetylation of arbekacin and antibiotic activity of its product. J. Antibiot. 49, 458-464. doi: 10.7164/antibiotics.49.458
49. Houghton, J. L., Green, K. D., Chen, W., and Garneau-Tsodikova, S. (2010). The future of aminoglycosides: the end or renaissance?. ChemBioChem 11, 880-902. doi: 10.1002/cbic.200900779
50. Iseman, M. D. (1994). Evolution of drug-resistant tuberculosis: a tale of two species. Proc. Natl. Acad. Sci. U.S.A. 91, 2428-2429. doi: 10.1073/pnas.91.7.2428
51. Jimenez, J.-M., Boyall, D., Brenchley, G., Collier, P. N., Davis, C. J., Fraysse, D., et al. (2013). Design and optimization of selective protein kinase C8 (PKC8) inhibitors for the treatment of autoimmune diseases. J. Med. Chem. 56, 1799-1810. doi: 10.1021/jm301465a
52. Kalan, L., and Wright, G. D. (2011). Antibiotic adjuvants: multicomponent anti-infective strategies. Expert Rev. Mol. Med. 13:e5. doi: 10.1017/S1462399410001766
53. Kao, S. J., You, I., Clewell, D. B., Donabedian, S. M., Zervos, M. J., Petrin, J., et al. (2000). Detection of the high-level aminoglycoside resistance gene aph(2")-Ib in Enterococcus faecium. Antimicrob. Agents Chemother. 44, 2876-2879. doi: 10.1128/AAC.44.10.2876-2879.2000
54. Karimi, R., and Ehrenberg, M. (1994). Dissociation rate of cognate peptidyl-tRNA from the A-Site of hyper-accurate and error-prone ribosomes. Eur. J. Biochem. 226, 355-360. doi: 10.1111/j.1432-1033.1994.tb20059.x
55. Kawaguchi, H., Naito, T., Nakagawa, S., and Fujisawa, K.-I. (1972). Bb-K8, a new semisynthetic aminoglycoside antibiotic. J. Antibiot. 25, 695-708. doi: 10.7164/antibiotics.25.695
56. Kim, S., Nguyen, C. M. T., Kim, E.-J., and Kim, K.-J. (2011). Crystal structure of Mycobacterium tuberculosis Rv3168: a putative aminoglycoside antibiotics resistance enzyme. Proteins 79, 2983-2987. doi: 10.1002/prot.23119
57. Koch, K. F., and Rhoades, J. A. (1970). Structure of nebramycin factor 6, a new aminoglycosidic antibiotic. Antimicrob. Agents Chemother. 10, 309-313.
58. Kondo, J., François, B., Russell, R. J. M., Murray, J. B., and Westhof, E. (2006). Crystal structure of the bacterial ribosomal decoding site complexed with amikacin containing the "-amino-a-hydroxybutyryl (haba) group. Biochimie 88, 1027-1031. doi: 10.1016/j.biochi.2006.05.017
59. Kondo, J., Pachamuthu, K., François, B., Szychowski, J., Hanessian, S., and Westhof, E. (2007). Crystal structure of the bacterial ribosomal decoding site complexed with a synthetic doubly functionalized paromomycin derivative: a new specific binding mode to an a-minor motif enhances in vitro antibacterial activity. ChemMedChem 2, 1631-1638. doi: 10.1002/cmdc.200700113
60. Kondo, S., and Hotta, K. (1999). Semisynthetic aminoglycoside antibiotics: development and enzymatic modifications. J. Infect. Chemother. 5, 1-9. doi: 10.1007/s101560050001
61. Kondo, S., Iinuma, K., Yamamoto, H., Maeda, K., and Umezawa, H. (1973). Syntheses of 1-N-{(S)-4-amino-2-hydroxybutyrl}-kanamycin B AND -3', 4"-dideoxykanamycin B active against kanamycin-resistant bacteria. J. Antibiot. 26, 412-415. doi: 10.7164/antibiotics.26.412
62. Lallemand, P., Leban, N., Kunzelmann, S., Chaloin, L., Serpersu, E. H., Webb, M. R., et al. (2012). Transient kinetics of aminoglycoside phosphotransferase (3')-IIIa reveals a potential drug target in the antibiotic resistance mechanism. FEBS Lett. 586, 4223-4227. doi: 10.1016/j.febslet.2012.10.027
63. Lambert, T., Gerbaud, G., Bouvet, P., Vieu, J. F., and Courvalin, P. (1990). Dissemination of amikacin resistance gene aphA6 in Acinetobacter spp. Antimicrob. Agents Chemother. 34, 1244-1248. doi: 10.1128/AAC.34.6.1244
64. Lambert, T., Gerbaud, G., and Courvalin, P. (1988). Transferable amikacin resistance in Acinetobacter spp. due to a new type of 3'-aminoglycoside phosphotransferase. Antimicrob. Agents Chemother. 32, 15-19. doi: 10.1128/AAC.32.1.15
65. Lambert, T., Gerbaud, G., Trieu-Cuot, P., and Courvalin, P. (1985). Structural relationship between the genes encoding 3'-aminoglycoside phosphotransferases in Campylobacter and in gram-positive cocci. Ann. Inst. Pasteur Microbiol. 136, 135-150. doi: 10.1016/S0769-2609(85)80040-5
66. Lee, K. Y., Hopkins, J. D., and Syvanen, M. (1991). Evolved neomycin phosphotransferase from an isolate of Klebsiella pneumoniae. Mol. Microbiol. 5, 2039-2046. doi: 10.1111/j.1365-2958.1991.tb00826.x
67. Lipsitch, M., Singer, R. S., and Levin, B. R. (2002). Antibiotics in agriculture: when is it time to close the barn door. Proc. Natl. Acad. Sci. U.S.A. 99, 5752-5754. doi: 10.1073/pnas.092142499
68. Lopez-Novoa, J. M., Quiros, Y., Vicente, L., Morales, A. I., and Lopez-Hernandez, F. J. (2011). New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int. 79, 33-45. doi: 10.1038/ki.2010.337
69. Lyutzkanova, D., Distler, J., and Altenbuchner, J. (1997). A spectinomycin resistance determinant from the spectinomycin producer Streptomyces flavopersicus. Microbiology 143, 2135-2143. doi: 10.1099/00221287-143-7-2135
70. Marks, L. R., Clementi, E. A., and Hakansson, A. P. (2012). The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents. PLoS ONE 7:e43514. doi: 10.1371/journal.pone.0043514
71. Martin, P., Jullien, E., and Courvalin, P. (1988). Nucleotide sequence of Acinetobacter baumannii aphA-6 gene: evolutionary and functional implications of sequence homologies with nucleotide-binding proteins, kinases and other aminoglycoside-modifying enzymes. Mol. Microbiol. 2, 615-625. doi: 10.1111/j.1365-2958.1988.tb00070.x
72. Matsuhashi, Y., Yagisawa, M., Kondo, S., Takeuchi, T., and Umezawa, H. (1975). Aminoglycoside 3'-phosphotransferases I and II in Pseudomonas aeruginosa. J. Antibiot. 28, 442-447. doi: 10.7164/antibiotics.28.442
73. Matt, T., Ng, C. L., Lang, K., Sha, S.-H., Akbergenov, R., Shcherbakov, D., et al. (2012). Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin. Proc. Natl. Acad. Sci. U.S.A. 109, 10984-10989. doi: 10.1073/pnas.1204073109
74. McKay, G. A., Thompson, P. R., and Wright, G. D. (1994). Broad spectrum aminoglycoside phosphotransferase type III from Enterococcus: overexpression, purification, and substrate specificity. Biochemistry 33, 6936-6944. doi: 10.1021/bi00188a024
75. Meier, A., Kirschner, P., Bange, F. C., Vogel, U., and Böttger, E. C. (1994). Genetic alterations in streptomycin-resistant Mycobacterium tuberculosis: mapping of mutations conferring resistance. Antimicrob. Agents Chemother. 38, 228-233. doi: 10.1128/AAC.38.2.228
76. Mishra, R. P., Oviedo-Orta, E., Prachi, P., Rappuoli, R., and Bagnoli, F. (2012). Vaccines and antibiotic resistance. Curr. Opin. Microbiol. 15, 596-602. doi: 10.1016/j.mib.2012.08.002
77. Moazed, D., and Noller, H. F. (1987). Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature 327, 389-394. doi: 10.1038/327389a0
78. Morita, Y., Tomida, J., and Kawamura, Y. (2012). MexXY multidrug efflux system of Pseudomonas aeruginosa. Front. Microbiol. 3:408. doi: 10.3389/fmicb.2012.00408
79. Nagabhushan, T. L., Cooper, A. B., Tsai, H., Daniels, P. J., and Miller, G. H. (1978). The syntheses and biological properties of 1-N-(S-4-amino-2-hydroxybutyryl)-gentamicin B and 1-N-(S-3-amino-2-hydroxypropionyl)-gentamicin B. J. Antibiot. 31, 681-687. doi: 10.7164/antibiotics.31.681
80. Nurizzo, D., Shewry, S. C., Perlin, M. H., Brown, S. A., Dholakia, J. N., Fuchs, R. L., et al. (2003). The crystal structure of aminoglycoside-3'-phospho-transferase-IIa, an enzyme responsible for antibiotic resistance. J. Mol. Biol. 327, 491-506. doi: 10.1016/S0022-2836(03)00121-9
81. Oka, A., Sugisaki, H., and Takanami, M. (1981). Nucleotide sequence of the kanamycin resistance transposon Tn903. J. Mol. Biol. 147, 217-226. doi: 10.1016/0022-2836(81)90438-1
82. Okazaki, A., and Avison, M. B. (2007). Aph(3')-IIc, an aminoglycoside resistance determinant from Stenotrophomonas maltophilia. Antimicrob. Agents Chemother. 51, 359-360. doi: 10.1128/AAC.00795-06
83. Ontario Medical Association. (2013). When antibiotics stop working. Ont. Med. Rev. 80, 27-43.
84. Pansegrau, W., Miele, L., Lurz, R., and Lanka, E. (1987). Nucleotide sequence of the kanamycin resistance determinant of plasmid RP4: homology to other aminoglycoside 3'-phosphotransferases. Plasmid 18, 193-204. doi: 10.1016/0147-619X(87)90062-X
85. Pape, T., Wintermeyer, W., and Rodnina, M. V. (2000). Conformational switch in the decoding region of 16S rRNA during aminoacyl-tRNA selection on the ribosome. Nat. Struct. Biol. 7, 104-107. doi: 10.1038/72364
86. Pardo, J. M., Malpartida, F., Rico, M., and Jiménez, A. (1985). Biochemical basis of resistance to hygromycin-B in Streptomyces hygroscopicus-the producing organism. J. Gen. Microbiol. 131, 1289-1298. doi: 10.1099/00221287-131-6-1289
87. Perlin, M. H., and Lerner, S. A. (1981). Localization of an amikacin 3'-phosphotransferase in Escherichia coli. J. Bacteriol. 147, 320-325.
88. Pompilio, A., Crocetta, V., Scocchi, M., Pomponio, S., Di Vincenzo, V., Mardirossian, M., et al. (2012). Potential novel therapeutic strategies in cystic fibrosis: antimicrobial and anti-biofilm activity of natural and designed a-helical peptides against Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. BMC Microbiol. 12:145-155. doi: 10.1186/1471-2180-12-145
89. Poole, K. (2005). Efflux-mediated antimicrobial resistance. J. Antimicrob. Chemother. 56, 20-51. doi: 10.1093/jac/dki171
90. Poole, K. (2011). Pseudomonas aeruginosa: resistance to the max. Front. Microbiol. 2:65. doi: 10.3389/fmicb.2011.00065
91. Prayle, A., and Smyth, A. R. (2010). Aminoglycoside use in cystic fibrosis: therapeutic strategies and toxicity. Curr. Opin. Pulm. Med. 16, 604-610. doi: 10.1097/MCP.0b013e32833eebfd
92. Ramirez, M. S., and Tolmasky, M. E. (2010). Aminoglycoside modifying enzymes. Drug Resist. Update 13, 151-171. doi: 10.1016/j.drup.2010.08.003
93. Ramon-Garcia, S., Otal, I., Martin, C., Gomez-Lus, R., and Ainsa, J. A. (2006). Novel streptomycin resistance gene from Mycobacterium fortuitum. Antimicrob. Agents Chemother. 50, 3920-3922. doi: 10.1128/AAC.00223-06
94. Rao, R. N., Allen, N. E., Hobbs, J. N. Jr., Alborn, W. E., Kirst, H. A., and Paschal, J. W. (1983). Genetic and enzymatic basis of hygromycin B resistance in Escherichia coli. Antimicrob. Agents Chemother. 24, 689-695. doi: 10.1128/AAC.24.5.689
95. Robicsek, A., Strahilevitz, J., Jacoby, G. A., Macielag, M., Abbanat, D., Park, C. H., et al. (2006). Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat. Med. 12, 83-88. doi: 10.1038/nm1347
96. Salauze, D., and Davies, J. (1991). Isolation and characterisation of an aminoglycoside phosphotransferase from neomycin-producing Micromonospora chalcea; comparison with that of Streptomyces fradiae and other producers of 4, 6-disubstituted 2-deoxystreptamine antibiotics. J. Antibiot. 44, 1432-1443. doi: 10.7164/antibiotics.44.1432
97. Salian, S., Matt, T., Akbergenov, R., Harish, S., Meyer, M., Duscha, S., et al. (2012). Structure-activity relationships among the kanamycin aminoglycosides: role of ring I hydroxy and amino groups. Antimicrob. Agents Chemother. 56, 6104-6108. doi: 10.1128/AAC.01326-12
98. Schatz, A., Bugle, E., and Waksman, S. A. (1944). Streptomycin, a substance exhibiting antibiotic activity against gram-positive and gram-negative bacteria. Proc. Soc. Exp. Biol. Med. 55, 66-69.
99. Scheeff, E. D., and Bourne, P. E. (2005). Structural evolution of the protein kinase-like superfamily. PLoS Comput. Biol. 1:e49. doi: 10.1371/journal.pcbi.0010049
100. Shakya, T., Stogios, P. J., Waglechner, N., Evdokimova, E., Ejim, L., Blanchard, J. E., et al. (2011). A small molecule discrimination map of the antibiotic resistance kinome. Chem. Biol. 18, 1591-1601. doi: 10.1016/j.chembiol.2011.10.018
101. Shakya, T., and Wright, G. D. (2010). Nucleotide selectivity of antibiotic kinases. Antimicrob. Agents Chemother. 54, 1909-1913. doi: 10.1128/AAC.01570-09
102. Shaul, P., Green, K. D., Rutenberg, R., Kramer, M., Berkov-Zrihen, Y., Breiner-Goldstein, E., et al. (2011). Assessment of 6'- and 6"'-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance. Org. Biomol. Chem. 9, 4057-4063. doi: 10.1039/c0ob01133a
103. Shaw, K. J., Rather, P. N., Hare, R. S., and Miller, G. H. (1993). Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. Microbiol. Rev. 57, 138-163.
104. Sheehan, J. C. (1967). The chemistry of synthetic and semisynthetic penicillins. Ann. N.Y. Acad. Sci. 145, 216-223. doi: 10.1111/j.1749-6632.1967.tb50220.x
105. Shi, K., and Berghuis, A. M. (2012). Structural basis for the dual nucleotide selectivity of aminoglycoside 2"-phosphotransferase IVa provides insight on determinants of nucleotide specificity of aminoglycoside kinases. J. Biol. Chem. 287, 13094-13102. doi: 10.1074/jbc.M112.349670
106. Shi, K., Houston, D. R., and Berghuis, A. M. (2011). Crystal structures of antibiotic-bound complexes of aminoglycoside 2"-phosphotransferase IVa highlight the diversity in substrate binding modes among aminoglycoside kinases. Biochemistry 50, 6237-6244. doi: 10.1021/bi200747f
107. Shinkawa, H., Sugiyama, M., and Nimi, O. (1987). The nucleotide sequence of a streptomycin 6-phosphotransferase gene from a streptomycin producer. J. Gen. Microbiol. 133, 1289-1296. doi: 10.1099/00221287-133-5-1289
108. Silver, L. L. (2011). Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24, 71-109. doi: 10.1128/CMR.00030-10
109. Smith, C. A., Toth, M., Frase, H., Byrnes, L. J., and Vakulenko, S. B. (2012). Aminoglycoside-2" phosphotransferase-IIIa (APH(2")-IIIa) prefers GTP over ATP: structural templates for nucleotide recognition in the bacterial aminoglycoside-2" kinases. J. Biol. Chem. 287, 12893-12903. doi: 10.1074/jbc.M112.341206
110. Sowadski, J., Epstein, L., Lankiewicz, L., and Karlsson, R. (1999). Conformational diversity of catalytic cores of protein kinases. Pharmacol. Ther. 82, 157-164. doi: 10.1016/S0163-7258(98)00054-0
111. Spellberg, B., Blaser, M., Guidos, R. J., Boucher, H. W., Bradley, J. S., Eisenstein, B. I., et al. (2011). Combating antimicrobial resistance: policy recommendations to save lives. Clin. Infect. Dis. 52, S397-S428. doi: 10.1093/cid/cir153
112. Stogios, P. J., Shakya, T., Evdokimova, E., Savchenko, A., and Wright, G. D. (2011). Structure and function of APH(4)-Ia, a hygromycin B resistance enzyme. J. Biol. Chem. 286, 1966-1975. doi: 10.1074/jbc.M110.194266
113. Suter, T. M., Viswanathan, V. K., and Cianciotto, N. P. (1997). Isolation of a gene encoding a novel spectinomycin phosphotransferase from Legionella pneumophila. Antimicrob. Agents Chemother. 41, 1385-1388.
114. Szychowski, J., Kondo, J., Zahr, O., Auclair, K., Westhof, E., Hanessian, S., et al. (2011). Inhibition of aminoglycoside-deactivating enzymes APH(3')-IIIa and AAC(6')-Ii by amphiphilic paromomycin O2"-ether analogues. ChemMedChem 6, 1961-1966. doi: 10.1002/cmdc.201100346
115. Taber, H. W., Mueller, J. P., Miller, P. F., and Arrow, A. S. (1987). Bacterial uptake of aminoglycoside antibiotics. Microbiol. Rev. 51, 439-457.
116. Tenover, F. C., and Elvrum, P. M. (1988). Detection of 2 different kanamycin resistance genes in naturally-occurring isolates of Campylobacter jejuni and Campylobacter coli. Antimicrob. Agents Chemother. 32, 1170-1173. doi: 10.1128/AAC.32.8.1170
117. Thompson, C. J., and Gray, G. S. (1983). Nucleotide sequence of a streptomycete aminoglycoside phosphotransferase gene and its relationship to phosphotransferases encoded by resistance plasmids. Proc. Natl. Acad. Sci. U.S.A. 80, 5190-5194. doi: 10.1073/pnas.80.17.5190
118. Thompson, P. R., Boehr, D. D., Berghuis, A. M., and Wright, G. D. (2002). Mechanism of aminoglycoside antibiotic kinase APH(3')-IIIa: role of the nucleotide positioning loop. Biochemistry 41, 7001-7007. doi: 10.1021/bi0256680
119. Thompson, P. R., Schwartzenhauer, J., Hughes, D. W., Berghuis, A. M., and Wright, G. D. (1999). The COOH terminus of aminoglycoside phosphotransferase (3')-IIIa is critical for antibiotic recognition and resistance. J. Biol. Chem. 274, 30697-30706. doi: 10.1074/jbc.274.43.30697
120. Toth, M., Chow, J. W., Mobashery, S., and Vakulenko, S. B. (2009). Source of phosphate in the enzymic reaction as a point of distinction among aminoglycoside 2"-phosphotransferases. J. Biol. Chem. 284, 6690-6696. doi: 10.1074/jbc.M808148200
121. Toth, M., Frase, H., Antunes, N. T., Smith, C. A., and Vakulenko, S. B. (2010). Crystal structure and kinetic mechanism of aminoglycoside phosphotransferase-2"-IVa. Protein Sci. 19, 1565-1576. doi: 10.1002/pro.437
122. Toth, M., Zajicek, J., Kim, C., Chow, J. W., Smith, C., Mobashery, S., et al. (2007). Kinetic mechanism of enterococcal aminoglycoside phosphotransferase 2"-Ib. Biochemistry 46, 5570-5578. doi: 10.1021/bi6024512
123. Trieu-Cuot, P., and Courvalin, P. (1986). Evolution and transfer of aminoglycoside resistance genes under natural conditions. J. Antimicrob. Chemother. 18(Suppl. C), 93-102.
124. Tsai, S. F., Zervos, M. J., Clewell, D. B., Donabedian, S. M., Sahm, D. F., and Chow, J. W. (1998). A new high-level gentamicin resistance gene, aph(2")-Id, in Enterococcus spp. Antimicrob. Agents Chemother. 42, 1229-1232.
125. Umezawa, H., Umezawa, S., Tsuchiya, T., and Okazaki, Y. (1971). 3', 4'-dideoxy-kanamycin B active against kanamycin-resistant Escherichia coli and Pseudomonas aeruginosa. J. Antibiot. 24, 485-487. doi: 10.7164/antibiotics.24.485
126. Vakulenko, S. B., and Mobashery, S. (2003). Versatility of aminoglycosides and prospects for their future. Clin. Microbiol. Rev. 16, 430-450. doi: 10.1128/CMR.16.3.430-450.2003
127. Vögtli, M., and Hütter, R. (1987). Characterisation of the hydroxystreptomycin phosphotransferase gene (sph) of Streptomyces glaucescens: nucleotide sequence and promoter analysis. Mol. Gen. Genet. 208, 195-203. doi: 10.1007/BF00330442
128. Wachino, J.-I., and Arakawa, Y. (2012). Exogenously acquired 16S rRNA methyltransferases found in aminoglycoside-resistant pathogenic gram-negative bacteria: an update. Drug Resist. Update 15, 133-148. doi: 10.1016/j.drup.2012.05.001
129. Welch, K. T., Virga, K. G., Whittemore, N. A., Ozen, C., Wright, E., Brown, C. L., et al. (2005). Discovery of non-carbohydrate inhibitors of aminoglycoside-modifying enzymes. Bioorg. Med. Chem. 13, 6252-6263. doi: 10.1016/j.bmc.2005.06.059
130. Wilson, J., John, C., Wong, T., Jayaraman, G., Sargeant, J., Papadopouos, A., et al. (2010). Strategies to control community-associated antimicrobial resistance among enteric bacteria and methicillin-resistant Staphylococcus aureus in Canada-executive summary. Can. J. Infect. Dis. Med. Microbiol. 21, 133-134.
131. World Economic Forum. (2013). Global Risks 2013, 8th Edn. Geneva: World Economic Forum.
132. World Health Organization. (2001). WHO Global Strategy for Containment of Antimicrobial Resistance. Geneva: World Health Organization.
133. Wright, J. J. (1976). Synthesis of 1-N-ethylsisomicin: a broad-spectrum semisynthetic aminoglycoside antibiotic. J. Chem. Soc. Chem. Commun. 6, 206-208. doi: 10.1039/c39760000206
134. Yokoyama, K., Doi, Y., Yamane, K., Kurokawa, H., Shibata, N., Shibayama, K., et al. (2003). Acquisition of 16S rRNA methylase gene in Pseudomonas aeruginosa. Lancet 362, 1888-1893. doi: 10.1016/S0140-6736(03)14959-8
135. Young, P., Walanj, R., Lakshmi, V., Byrnes, L., Metcalf, P., Baker, E., et al. (2009). The crystal structures of substrate and nucleotide complexes of Enterococcus faecium aminoglycoside-2"-phosphotransferase-IIa [APH(2")-IIa] provide insights into substrate selectivity in the APH(2") sub-family. J. Bacteriol. 191, 4133-4143. doi: 10.1128/JB.00149-09
136. Zalacain, M., González, A., Guerrero, M. C., Mattaliano, R. J., Malpartida, F., and Jiménez, A. (1986). Nucleotide sequence of the hygromycin B phosphotransferase gene from Streptomyces hygroscopicus. Nucleic Acids Res. 14, 1565-1581. doi: 10.1093/nar/14.4.1565
137. Zuccotto, F., Ardini, E., Casale, E., and Angiolini, M. (2010). Through the "gatekeeper door": exploiting the active kinase conformation. J. Med. Chem. 53, 2681-2694. doi: 10.1021/jm901443h