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Chapter 1 : Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications

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Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications, Page 1 of 2

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Abstract:

This chapter focuses on varied mechanisms by which aminoglycosidemodifying enzymes (AMEs) confer resistance to aminoglycosides. Clinical resistance to aminoglycosides emerges by one of four mechanisms: (i) loss of cell permeability (decreased uptake); (ii) alterations in the target site (ribosome) that prevent binding; (iii) expulsion by efflux pumps; and (iv) enzymatic inactivation by AMEs. Inhibition of AMEs by drugs such as dibekacin (a semisynthetic aminoglycoside), 5-epi-sisomicin, and 5-epi-gentamicin is discussed in the chapter that ensues. The major thrust of current efforts at AME inhibition has targeted the APH enzymes. Dimeric aminoglycosides and construction of amino-glycosides that undergo a cyclic process of phosphorylation and release of inorganic phosphate are exciting developments. In understanding these mechanisms, the reader should keep in mind the microbiological difference between in vitro synergism and clinical trials showing the benefits of synergistic therapy. Studies of the structure of the ribosome have resulted in an intense interest in aminoglycosides and macrolides as therapeutic agents. The lessons learned from the study of the mechanism of action and resistance of these agents will undoubtedly lead to further development of novel inhibitors of protein synthesis.

Citation: Bonomo R. 2007. Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications, p 3-6. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch1
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References

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1. Daniel, T. M. 2005. Selman Abraham Waksman and the discovery of streptomycin. Int. J. Tuberc. Lung Dis. 9: 120122.
2. Francioli, P. 1995. Antibiotic treatment of streptococcal and enterococcal endocarditis: an overview. Eur. Heart J. 16(Suppl. B): 7579.
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4. Le, T., and, A. S. Bayer. 2003. Combination antibiotic therapy for infective endocarditis. Clin. Infect. Dis. 36: 615621.
5. Nguyen, M., and, E. P. Chung. 2005. Telithromycin: the first ketolide antimicrobial. Clin. Ther. 27: 11441163.
6. Paul, M.,, I. Benuri-Silbiger,, K. Soares-Weiser, and, L. Leibovici. 2004. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 328: 668.
7. Vakulenko, S. B., and, S. Mobashery. 2003. Versatility of ami-noglycosides and prospects for their future. Clin. Microbiol. Rev. 16: 430450.

Tables

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Table 1.1

Aminoglycosides in clinical use and their source

Citation: Bonomo R. 2007. Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications, p 3-6. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch1
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Table 1.2

Examples of in vitro synergy of aminoglycosides and cell wall active agents

Citation: Bonomo R. 2007. Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications, p 3-6. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch1
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Table 1.3

Mechanisms of resistance to macrolides in and

Citation: Bonomo R. 2007. Overview of Aminoglycosides and Enzyme-Mediated Bacterial Resistance, Clinical Implications, p 3-6. In Bonomo R, Tolmasky M (ed), Enzyme-Mediated Resistance to Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555815615.ch1

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