A Molecular basis for human hypersensitivity of aminoglyscoside antibiotics

Open Access
Publisher Website
Google Scholar
Abstract
We have investigated the distribution of mitochondrial DNA polymorphisms in a rare maternally transmitted genetic trait that causes hypersensitivity to aminoglycoside antibiotics, In the hope that a characterization of Its molecular basis might provide a molecular and cellular understanding of amlnoglycoside-induced deafness (AGD). Here we report that the frequency of a particular mitochondrial DNA polymorphism, 1555°, Is associated nonrandomly with aminoglycoslde-lnduced deafness in two Japanese pedigrees, bringing the frequency of this polymorphism to 5 occurrences In 5 pedigrees of AGD, and in 4 of 78 sporadic cases In which deafness was thought to be the result of aminoglycoside exposure; both frequencies are significantly different from the occurrence of this mutation In the hearing population, which was 0 In 414 individuals surveyed. The 1555G polymorphism occurred In none of 34 amlnoglycoslderesistant Individuals. We propose a specific molecular mechanism for aminoglycoside hypersensitivity in individuals carrying the 1555G polymorphism, based on the three-dimensional structure of the rlbosome, in which the 1555° polymorphism favors aminoglycoside binding sterically, by increasing access to the therlbosome cleft.