engleski

Antimicrobial resistance conferred by changes in rRNA methylation

Many antibiotics widely used in clinical settings prevent the process of protein synthesis by binding to functionally important regions on bacterial ribosome. A wealth of recently obtained structural data has revealed that rRNA is the key element responsible for both the peptide bond synthesis and the crucial interactions with antibiotics. It is therefore to expect that changes that confer antibiotic resistance are mainly found in the rRNA. In contrast to RNA mutations that are found only in a portion of the rRNA genes, the methylation of a specific nucleotide within the rRNA is most common mechanism of resistance to ribosome-targeting drugs in pathogenic bacteria with multiple rRNA operons. Methyltransferases (MTases) responsible for these modifications modify all rRNA copies and thus generate high level of resistance. A large fraction of clinical pathogens resistant to macrolide antibiotics contain MTases from Erm family that methylate A2058 in the 23S rRNA. These enzymes are genetically and biochemically well characterised, yet no specific inhibitor that would block this type of resistance is on the market. In addition, there is a number of other less explored resistance MTases that target the 50S subunit: the tylosin resistance MTase RlmAII specific for G748, the thiostrepton resistance MTase Tsr that modifies A1067 and orthosomycin resistance MTases EmtA, AviRb, and AviRa that modify G2470, U2479 and G2535 respectively. The 30S subunit is a target for aminoglycosides and tetracyclines. Many different resistance mechanisms to these antibiotics have been described in clinical strains, but until recently the methylation of rRNA was not among them. In the last few years, however, new types of highly aminoglycoside resistant pathogens have emerged that carry Arm and Kam MTases, specific for G1405 and A1408, respectively, and were previously restricted exclusively to antibiotic producers. Several genes have recently been isolated from plasmids that are now rapidly spreading by horizontal transfer, thus representing a threat to successful treatment of bacterial infections. Our recent studies on sequence-structure-function relationships of resistance MTases will be presented and discussed. Present data will form a basis for the rational design of effective novel compounds that would inhibit these enzymes and help us to continue the common use of ribosomal antibiotics.

antibiotic resistance; rRNA methylation

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