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NRC of Aminoclycoside resistance





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2010 [fr] [nl]
2009 [fr] [nl]
2008 [fr] [nl]





Project leader: Dr R. Vanhoof



Aminoglycosides have been used extensively for a long time in the clinical practice. They have been regarded as irreplaceable compounds in the anti-infective armamentarium despite the apparently never ending proliferation of other anti-infective derivatives. The name "aminoglycoside" is derived from the fact that most of these compounds (spectinomycin is an exception) contain one or more aminosugars in their structure. Aminoglycosides have a diaminocyclitol nucleus to which the aminosugars are linked. The aminosugar attached to the 4 position receives primed numbers (') and are numbered from 1' to 6'. The sugars attached to the 5 or 6 position receive a double primed numbering ("), and are hence numbered from 1" to 6". The positions in the cyclitol moiety are numbered 1 - 6 (Figure 1).

Basically, aminoglycosides have a broad antimicrobial spectrum including staphylococci and aerobic and facultative aerobic Gram-negative bacilli.


Resistance Mechanisms

The most important resistance mechanisms are (i) target resistance, (ii) permeability and efflux resistance and (iii) the presence of Aminoglycoside Modifying Enzymes (AMEs). Target resistance is due to the presence of ribosomes with decreased affinity for the aminoglycosides as a result of a mutation. The high level streptomycin resistance resulted from a single step mutation in the strA (rpsL) locus which encodes the S12 protein.
The mechanism of permeability resistance has not been elucidated completely yet. Any alteration affecting the aminoglycoside transport system can lead to a reduced intracellular uptake of the aminoglycosides resulting in resistance. Furthermore, this type of resistance can also be due to the presence of an efflux system.

Resistance by aminoglycoside modifying enzymes is by far the most frequently encountered mechanism and is very often plasmid or transposon mediated. This explains the wide dissemination of the genetic determinants of these enzymes. Aminoglycosides contain amino and hydroxyl groups that can be modified by these enzymes. At present, three groups of enzymes are recognized, i.e. Aminoglycoside phosphoryltransferases (APH), the Aminoglycoside nucleotidyltransferases (ANT) and the Aminoglycoside acetyltransferases (AAC). A particular class of enzymes is further characterized by the location of the C-atom at which modification occurs, e.g. AAC(3), AAC(6'), AAC(2').








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