23S rRNA 2058A-->G alteration mediates ketolide resistance in combination with deletion in L22.

Abstract:

:Resistance to macrolides and ketolides occurs mainly via alterations in RNA moieties of the drug-binding site. Using an A2058G mutant of Mycobacterium smegmatis, additional telithromycin resistance was acquired via deletion of 15 residues from protein L22. Molecular modeling, based on the crystal structure of the large ribosomal subunit from Deinococcus radiodurans complexed with telithromycin, shows that the telithromycin carbamate group is located in the proximity of the tip of the L22 hairpin-loop, allowing for weak interactions between them. These weak interactions may become more important once the loss of A2058 interactions destabilizes drug binding, presumably resulting in a shift of the drug toward the other side of the tunnel, namely, to the vicinity of L22. Hence, the deletion of 15 residues from L22 may further destabilize telithromycin binding and confer telithromycin resistance. Such deletions may also lead to notable differences in the tunnel outline, as well as to an increase of its diameter to a size, allowing the progression of the nascent chain.

authors

Berisio R,Corti N,Pfister P,Yonath A,Böttger EC

doi

10.1128/AAC.00767-06

subject

Has Abstract

pub_date

2006-11-01 00:00:00

pages

3816-23

issue

11

eissn

0066-4804

issn

1098-6596

pii

AAC.00767-06

journal_volume

50

pub_type

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