The outward shift of clarithromycin binding to the ribosome in mutantHelicobacter pyloristrains
HELICOBACTER(2020)
Abstract
Objectives Disruption of protein synthesis, by drug-mediated restriction of the ribosomal nascent peptide exit tunnel (NPET), may inhibit bacterial growth. Here, we have studied the secondary and tertiary structures of domain V of the 23S rRNA in the wild-type and mutant (resistant)H. pyloristrains and their mechanisms of interaction with clarithromycin (CLA). Methods H pyloristrains, isolated from cultured gastric biopsies, underwent CLA susceptibility testing by E test, followed by PCR amplification and sequencing of domain V of 23S rRNA. The homology model of this domain inH pylori, in complex with L4 and L22 accessory proteins, was determined based on theE. coliribosome 3D structure. The interactions between CLA and 23S rRNA complex were determined by molecular docking studies. Results Of the 70H pyloristrains, isolated from 200 dyspeptic patients, 11 (16%) were CLA-resistant. DNA sequencing identified categories with no (A), A2142G (B), and A2143G (C) mutations. Docking studies of our homology model of 23S rRNA complex with CLA showed deviated positions for categories B and C, in reference to category A, with 12.19 angstrom and 7.92 angstrom RMSD values, respectively. In both mutant categories, CLA lost its interactions at positions 2142 and 2587 and gained two new bonds with the L4 accessory protein. Conclusion Our data suggest that, in mutantH pyloristrains, once the nucleotides at positions 2142 and 2587 are detached from the drug, CLA interacts with and is peeled back by the L4 accessory protein, removing the drug-imposed spatial restriction of the NPET.
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Key words
23S rRNA mutation,A2142G(A2058(E coli)),A2143G(A2059(E coli)),A2587(A2503(E coli)),clarithromycin resistance,H pylori
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