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Antimicrobial Agents and Chemotherapy, November 2009, p. 4612-4618, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00965-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Interaction of Aminoglycosides with Human Mitochondrial 12S rRNA Carrying the Deafness-Associated Mutation{triangledown}

Yaping Qian1 and Min-Xin Guan1,2*

Division of Human Genetics, Cincinnati Children's Hospital Medical Center,1 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio2

Received 21 July 2008/ Returned for modification 12 November 2008/ Accepted 12 August 2009

The mitochondrial 12S rRNA A1555G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we employed an RNA-directed chemical-modification approach to understanding the pathogenesis of aminoglycoside-induced hearing loss. The patterns of chemical modification of RNA oligonucleotides carrying the A1555G mutation by dimethyl sulfate (DMS) were distinct from those of the RNA oligonucleotides carrying wild-type sequence in the presence of aminoglycosides. In the RNA analogue carrying the A1555G mutation, reduced reactivity to DMS occurred in base G1555 as well as in bases C1556 and A1553 in the presence of paromomycin, neomycin, gentamicin, kanamycin, tobramycin, or streptomycin. In particular, base G1555 exhibited marked but similar levels of protection in the presence of 0.1 µM to 100 µM neomycin, gentamicin, or kanamycin. In contrast, the levels of protection in base G1555 appeared to be correlated with the concentration of paromycin, tobramycin, or steptomycin. Furthermore, increasing reactivities to DMS in the presence of these aminoglycosides were observed for bases A1492, C1493, C1494, and A1557 in the RNA analogue carrying the A1555G mutation. These data suggested that the A1555G mutation altered the binding properties of aminoglycosides at the A site of 12S rRNA and led to local conformational changes in 12S rRNA carrying the A1555G mutation. The interaction between aminoglycosides and 12S rRNA carrying the A1555G mutation provides new insight into the pathogenesis of aminoglycoside ototoxicity.

* Corresponding author. Mailing address: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Phone: (513) 636-3337. Fax: (513) 636-2261. E-mail: min-xin.guan{at}cchmc.org

{triangledown} Published ahead of print on 17 August 2009.

Antimicrobial Agents and Chemotherapy, November 2009, p. 4612-4618, Vol. 53, No. 11
0066-4804/09/$08.00+0     doi:10.1128/AAC.00965-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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