Interaction of aminoglycosides with human mitochondrial 12S rRNA carrying the deafness-associated mutation

Y Qian, MX Guan - Antimicrobial agents and chemotherapy, 2009 - Am Soc Microbiol
Antimicrobial agents and chemotherapy, 2009Am Soc Microbiol
ABSTRACT 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 …
Abstract
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.
American Society for Microbiology