engleski

Antibiotic resistance by RNA methylation

RNA molecules undergo posttranscriptional modifications as a part of their maturation process. Of several modifications found in ribosomal RNA, methylation is the most frequent one. In addition to this basic set of modifications, some antibiotic producing bacteria as well as many clinical strains utilise the common mechanism of RNA methylation to protect the protein synthesis machinery from the destructive action of their own metabolites. In contrast to other mechanisms, like RNA mutations that are found only in a portion of the rRNA genes, the methylation of antibiotic target is an extremely efficient mechanism, since it modifies all rRNA copies and generates high level of resistance. It has been found that the action of two main classes of antibiotics can be prevented by enzymatic activity of rRNA methyltransferases (MTases) ; these are macrolide-lincosamide-streptogramin B (MLS) and aminoglycoside antibiotics. The most prevalent mechanism of the MLS resistance is exhibited by the action of the enzymes from the erythromycin ribosome methylase (Erm) family. Erm enzymes methylate specific adenine residue within 23S rRNA, thus preventing antibiotic binding to the ribosome. The results of the recent studies on the identification of the Erm(C) binding site on the 23S RNA will be presented. Direct application of these results in design of the specific inhibitor of Erm MTases will be discussed and put in perspective to propose new directions to overcome the threatening problem of MLS resistance. The self-defense mechanism of natural producers of deoxystreptamine-containing aminoglycoside antibiotics is methylation of a specific guanine residue within the 16S rRNA. In addition, this is a new mechanism of resistance found in members of clinically important Enterobacteriaceae family and in Pseudomonas aeruginosa and Serratia marcescens clinical strains. Methylation of 16S rRNA in aminoglycoside resistant bacteria is carried out by MTases from the Agr family. The available data on the Agr methylases are extremely scarce. Biochemical and experimental structural data on these enzymes virtually do not exist, as well as any data on the substrate requirements. All studies that would give us insight into mechanism of action of these enzymes are therefore absolutely essential.

antibiotic resistance; RNA methylation; Erm methyltransferases; Agr methyltransferases

nije evidentirano