Aminoglycosides (Streptomycin, kanamycin, tobramycin, amikacin,...) are compounds
that are characterized by the presense of an aminocyclitol ring linked to aminosugars
in their structure. Their bactericidal activity is attributed to the irreversible
binding to the ribosomes although their interaction with other cellular structures
and metabolic processes has also been considered. They have a broad antimicrobial
spectrum. They are active against aerobic and facultative aerobic Gram-negative bacilli
and some Gram-positive bacteria of which staphylococci. Aminoglycosides are not active
against anaerobes and rikettsia. Spectinomycin which is an aminocyclitol devoided
of aminosugars is by extension included in the familiy of aminoglycosides. It also
differs from them by its bacteriostatic ativity and by its way of action. Spectinomycin
acts on protein synthesis during the mRNA-ribosome interaction and it does not lead
to mistranslation like aminoglycosides do.
Three mechanisms of resistance have been recognized, namely ribosome alteration,
decreased permeability, and inactivation of the drugs by aminoglycoside modifying
enzymes. The latter mechanism is of most clinical importance since the genes encoding
aminoglycoside modifying enzymes can be disseminated by plasmids or transposons.
Ribosome alteration
High level resistance to streptomycin and spectinomycin can result from single step
mutations in chromosomal genes encoding ribosomal proteins: rpsL (or strA),
rpsD (or ramA or sud2), rpsE (eps or
spc or spcA). Mutations in strC (or strB) generate a
low-level streptomycin resistance.
Decreased permeability
Absence of or alteration in the aminoglycoside transport system, inadequate membrane
potential, modification in the LPS (lipopolysacchaccarides) phenotype can result
in a cross resistance to all aminoglycosides.
Inactivation of aminoglycosides
These enzymes are classified into three major classes according to the type modification:
AAC (acetyltransferases), ANT (nucleotidyltransferases or adenyltransferases), APH
(phosphotransferases). This classification was extensively reviewed by Shaw
et al. (1993).
ant(3'')-Ia (synonyms: aadA, aad(3'')(9))confers
resistance to streptomycin and spectinomycin. The gene has been found in association
with several transposons (Tn7, Tn21, ...) and is ubiquitous
among gram-negative bacteria.
aph(3')-II (synonyms: aphA-2, nptII) confers
resistance to Km (Kanamycin), Neo (Neomycin), Prm (Paromomycin), Rsm (Ribostamycin),
But (Butirosin), GmB (GentamycinB). This gene is rarely found in clinical isolates.
aph(3')-II is associated with transposon Tn5 and observed in
gram-negative bacteria and Pseudomonas sp. However, its relative abundance
in environmental KanR isolates seems to be low (Recorbet
et al., 1992; Leff et al., 1993; Smalla
et al., 1993).
aph(3')-III (synonyms: nptIII) confers
resistance to Km (Kanamycin), Neo (Neomycin), Prm (Paromomycin), Rsm (Ribostamycin),
Lvdm (Lividomycin), But (Butirosin), GmB (GentamycinB). Amk (Amikacin) and Isp (Isepamicin)
are also modified in vitro, but according to the susceptibility standards
established by NCCLS resistance is only expressed at a low level by many strains.
aph(3')-III is commonly distributed among gram-positive bacteria but has also
been observed in Campylobacter spp.
nptIII is not frequent in molecular biology but can be found on some Agrobacterium
vectors for plant transformation (Bevan, 1984).
Aminoglycoside
Modifying Enzymes (Copyrights © by WARN Development)
Aminoglycoside
antibacterials (Copyrights © by Purdue Research Foundation)
Aminoglycosides
(link to the University of Winconsin Hospital)
Bevan, M. 1984. Binary Agrobacterium vectors for plant transformation.
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Flamm, R. K., K. L. Phillips, F. C. Tenover, and J. J. Plorde. 1993. A survey of clinical isolates of Enterobacteriaceae using a series
of DNA probes for aminoglycoside resistance genes. Mol. Cell Probes. 7:139-144.
Review.
Leff, L. G., J. R. Dana, J. V. Mc Arthur; and L. J. Shimkets.
1993. Detection of Tn5-like sequences in kanamycin-resistant stream
bacteria and environmental DNA. Appl. Environ. Microbiol. 59:417-421.
Miller, G. H., F. J. Sabatelli, L. Naples, R. S. Hare, and K. J. Shaw. 1995. The changing nature of aminoglycoside resistance mechanisms and the
role of isepamicin--a new broad-spectrum aminoglycoside. The Aminoglycoside Resistance
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Miller, G. H., F. J. Sabatelli, R. S. Hare, Y. Glupczynski, P. Mackey, D. Shlaes,
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time and geographic area: a reflection of aminoglycoside usage patterns? Aminoglycoside
Resistance Study Groups. Clin. Infect. Dis. 24 Suppl 1:S46-S62.
Recorbet, G., A. Givaudan, C. Steinberg, R. Bally, P. Normand,
and G. Faurie. 1992. Tn5 to assess soil fate of genetically marked bacteria:
screening for aminoglycoside resistance advantage and labelling specificity. FEMS
Microbiol. Ecol. 86:187-194. No abstract available.
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isolates of enterococci. Appl. Environ. Microbiol. 61:374-376.
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relationships of the aminoglycoside-modifying enzymes. Microbiol. Rev. 57:138-163.
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from different environments. FEMS Microbiol. Ecol. 13:47-58. No abstract available.
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results of surveys in eight regions of the world. J. Chemother. 7 Suppl 2:17-30.
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Agents Chemother. 37:927-928. No abstract available.
van Elsas and K. Smalla. 1995. Antibiotic (kanamycin and streptomycin) resistance traits in the
environment. Presented at the Workshoop on "Key Biosafety Aspects of Genetically
modified Organisms. Braunschweig, Germany.
Khan, M. S., and P. Maliga. 1999. Fluorescent
antibiotic resistance marker for tracking plastid transformation in higher plants.
Nat. Biotechnol. 17(9):910-915.
Schmitz, F. J., J. Verhoef, and A. C. Fluit. 1999. Prevalence
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in the European SENTRY Antimicrobial Surveillance Programme. Eur. J. Clin.
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Recht, M. I., S. Douthwaite, and J. D.Puglisi. 1999. Basis
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activity and resistance. Antimicrob. Agents Chemother. 43(4):727-737. No
abstract available.