engleski

Interaction of aminoglycoside resistance methyltransferases with bacterial ribosome

A substantial number of potent and widely used antibiotics inhibit the bacterial cell growth by interfering with the essential cellular process of translation. From early cross-linking and chemical foot printing experiments it has been learned that antibiotics bind to functionally important parts of the ribosome, such as the peptidyl transferase center, the peptide exit tunnel and the GTPase segment in the 50S subunit, or to the decoding and tRNA binding sites in the 30S subunit. With the advances in ribosome crystallography many of the atomic aspects have been revealed that offer a detailed view of different snapshots in protein synthesis, as well as of the interaction of ribosomal antibiotics with the ribosome. We now know that the ribosomal RNA is responsible both for the enzymatic properties of the ribosome and for most of the contacts with the 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. 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, which 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 aminoglycoside resistance MTases will be presented and discussed. Our latest results will be put in perspective with the rational design of effective novel compounds that would inhibit these enzymes and help us to continue the common use of ribosomal antibiotics.

aminoglycoside antibiotics; 16S rRNA methylation; methyltransferase Sgm

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