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AMINOGLYCOSIDE RESISTANCE BY TARGET MODIFICATION

Mutation of Targets
Aminoglycosides interfere with translational fidelity by binding to the 30S ribosomal subunit [1]. Most aminoglycoside antibiotics of the 2-deoxystreptamine aminocyclitol class like neomycin and gentamicin bind specifically to the 16S rRNA in the codon-decoding A-site, resulting in impairment of codon–anticodon pairing (Figure 1) [2-5]. As a consequence point mutations in the 16S rRNA can result in resistance to aminoglycosides [6]. For the 2-deoxystreptamine antibiotics (gentamicin, tobramycin, kanamycin B, amikacin, isepamicin, arbekacin, neomycin), mutations of A1408 (E. coli numbering) confer high-level resistance [7-8]. Figure 2 shows the interaction of aminoglycosides with the acceptor site of the 30S ribosome.

Figure 1. aminoglycosides that bind specifically to the 16S rRNA in the codon-decoding A-site.

 

Figure 2. Interaction of aminoglycosides with the acceptor site of the 30S ribosome. Paromomycin and streptomycin interactions with the 16S rRNA and ribosomal protein S12.

Antibiotics bearing the streptamine aminocyclitol bind in the codon-decoding site, and make multiple contacts to rRNA and proteins such as S12. Consequently, mutations in 16S rRNA and the ribosomal protein RpsL (S12) result in high-level resistance [9-10].

Also remote mutations could confer resistance to aminoglycosides like the single point mutation A1408 [11] or mutation in ribosomal protein S4 [12]. 

Enzyme catalyzed target mutations

Ribosomal methylation in aminoglycoside producers frequently result in high level of resistance. The gentamicin producer Micromonospora purpurea [13] and the tobramycin producer Streptomyces tenebrarius [14],  encode S-adenosyl methionine-dependent methyltransferases that modify G1405 or A1408 of the 16S rRNA to the 7-methyl derivative [15]. Generally the rRNA methylation confers very-high-level resistance to aminoglycosides (MICs > 0.5 mg/ml) and was confined to nonpathogenic actinomycetes. However, in 2003, the
first description of a 16S rRNA methyltransferase, RmtA, conferring resistance to 4,6-disubstituted 2-deoxystreptamine aminoglycosides in a clinical isolate of Pseudomonas aeruginosa was reported [16]. Similar genes, termed arm, from Serratia marcescens [17], Klebsiella pneumoniae [18], and Escherichia coli [19] have been also reported. The genes in Enterobacteriaceae are encoded on transposons [20-21] and in Pseudomonas on R-plasmids [22] facilitating dissemination.

 


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