Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2'-O-methylations in 16S and 23S rRNAs.

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Johansen SK, Maus CE, Plikaytis BB, Douthwaite S

Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2'-O-methylations in 16S and 23S rRNAs.

Mol Cell. 2006 Jul 21;23(2):173-82.

PubMed ID

16857584 [ View in PubMed

]

Abstract

The cyclic peptide antibiotics capreomycin and viomycin are generally effective against the bacterial pathogen Mycobacterium tuberculosis. However, recent virulent isolates have become resistant by inactivation of their tlyA gene. We show here that tlyA encodes a 2'-O-methyltransferase that modifies nucleotide C1409 in helix 44 of 16S rRNA and nucleotide C1920 in helix 69 of 23S rRNA. Loss of these previously unidentified rRNA methylations confers resistance to capreomycin and viomycin. Many bacterial genera including enterobacteria lack a tlyA gene and the ensuing methylations and are less susceptible than mycobacteria to capreomycin and viomycin. We show that expression of recombinant tlyA in Escherichia coli markedly increases susceptibility to these drugs. When the ribosomal subunits associate during translation, the two tlyA-encoded methylations are brought into close proximity at interbridge B2a. The location of these methylations indicates the binding site and inhibitory mechanism of capreomycin and viomycin at the ribosome subunit interface.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Capreomycin	16S/23S rRNA (cytidine-2'-O)-methyltransferase TlyA	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Yes	Inhibitor	Details

Polypeptides

Name	UniProt ID
16S/23S rRNA (cytidine-2'-O)-methyltransferase TlyA	P9WJ63	Details